
==== Front
Diabetol Metab Syndr
Diabetol Metab Syndr
Diabetology & Metabolic Syndrome
1758-5996
BioMed Central London

39289758
1466
10.1186/s13098-024-01466-x
Review
Therapeutic potential of finerenone for diabetic cardiomyopathy: focus on the mechanisms
Wang Jing 1
Xue Haojie 1
He Jinyu 1
Deng Li 2
Tian Julong 3
Jiang Yang jy93954924@qq.com

1
Feng Jian jerryfeng@swmu.edu.cn

1
1 https://ror.org/0014a0n68 grid.488387.8 Department of Cardiology, Stem Cell Immunity and Regeneration Key Laboratory of Luzhou, The Affiliated Hospital of Southwest Medical University; Southwest Medical University Affiliated Hospital Medical Group Gulin Hospital (Gulin County People’s Hospital), Luzhou, Sichuan China
2 https://ror.org/0014a0n68 grid.488387.8 Department of Rheumatology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan China
3 https://ror.org/01h8y6y39 grid.443521.5 0000 0004 1790 5404 Department of Cardiology, The Affiliated Hospital of Panzhihua University, Panzhihua, Sichuan China
18 9 2024
18 9 2024
2024
16 23216 7 2024
6 9 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Diabetic cardiomyopathy (DCM) is a kind of myocardial disease that occurs in diabetes patients and cannot be explained by hypertensive heart disease, coronary atherosclerotic heart disease and other heart diseases. Its pathogenesis may be closely related to programmed cell death, oxidative stress, intestinal microbes and micro-RNAs. The excessive activation of mineralocorticoid receptors (MR) in DCM can cause damage to the heart and kidneys. The third-generation non-steroidal mineralocorticoid receptor antagonist (MRA), finerenone, can effectively block MR, thus playing a role in protecting the heart and kidneys. This review mainly introduces the classification of MRA, and the mechanism of action, applications and limitations of finerenone in DCM, in order to provide reference for the study of treatment plans for DCM patients.

Keywords

Finerenone
Diabetic cardiomyopathy
Programmed cell death
Oxidative stress
Intestinal microbiota
Sichuan Science and Technology Program2022YFS0610 Luzhou Municipal People’s Government - Southwest Medical University Science and Technology Strategic Cooperation2021LZXNYD-J33 Hejiang County People's Hospital - Southwest Medical University Science and Technology Strategic Cooperation Project2021HJXNYD13 2021HJXNYD04 2022HJXNYD05 Xuyong County People's Hospital - Southwest Medical University Science and Technology Strategic Cooperation Project2024XYXNYD18 Gulin County People's Hospital - Affiliated Hospital of Southwest Medical University Science and Technology strategic Cooperation2022GLXNYDFY13 China International Medical Foundation2022-N-01-33 issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
==== Body
pmcClassification of mineralocorticoid receptor antagonists

Aldosterone is the main mineralocorticoid that can bind to the mineralocorticoid receptor (MR) to maintain water and electrolyte balance and induce pro-inflammatory activity in the body, and ultimately lead to dysfunction and failure of target organs such as the heart and kidneys [1, 2].

Mineralocorticoid receptor antagonists (MRAs) can inhibit the excessive activation of MR, thereby playing a role in protecting the heart and kidneys [3, 4]. According to molecular structure, MRA can be divided into traditional steroidal MRA and new generation non-steroidal MRA [5]. Steroid MRA mainly includes spironolactone and eplerenone, which have steroidal structures. However, spironolactone has low selectivity for MR and a higher incidence of hyperkalemia after administration [6]. Eplerenone has higher selectivity for MR, stronger anti aldosterone activity and lower side effects than spironolactone [7]. Non-steroidal MRA mainly includes finerenone, Esaxerenone, AZD9977, Aparenone, and KBP-5074, which have non steroidal structures [5, 8]. Finerenone has high selectivity for MR and is less prone to side effects such as hyperkalemia [9].

Mechanism and function of finerenone in diabetic cardiomyopathy

Diabetic cardiomyopathy (DCM) is an organic heart disease resulting from abnormal myocardial structure and function in individuals with DM who do not have other conditions, such as coronary artery disease, hypertension, valvular heart disease and congenital heart disease. DCM arises due to dysregulated glucose and lipid metabolism associated with DM, triggering the activation of various inflammatory pathways [10]. Research has found that DCM is closely related to programmed cell death, oxidative stress, intestinal microbiota, and MicroRNAs (miRNAs) [11–14]. Finerenone is a non-steroidal MRA, and there is extensive research evidence (Phase III study FIDELIO/FIGARO) indicating that finerenone can provide protective effects on the heart and kidneys [15]. As a type of MRA, finerenone can affect programmed cell death [16]. By blocking the MR, finerenone may also inhibit the generation of reactive oxygen species (ROS), which promote oxidative stress in cells, leading to tissue injury [4] (Table 1). However, further research is needed to investigate the relationship between finerenone and intestinal microbiota as well as miRNAs.Table 1 Basic science trials of finerenone

Target	Organ and tissue	Model	Effect	
TNFa/TNFR1/CASPASE8	Heart	High-fat diet/low-dose streptozotocin-induced diabetic rats	Reduce the apoptosis of cardiomyocytes [16]	
PPARγ/CD36	Heart	High-fat diet/low-dose streptozotocin-induced diabetic rats	Improve lipid metabolism in cardiomyocytes; inhibit apoptosis and oxidative stress [16]	
GRK5	H9c2 cardiomyocytes	Cells endogenously express the MR and GRK5	Inhibit apoptosis, oxidative stress, and fibrosis [17]	
MR	Human coronary artery SMCs and umbilical vein ECs	Cells were incubated with aldosterone	Reduce SMC proliferation and EC apoptosis [18]	
PI3K/Akt/eNOS	Kidney	High-fat diet/streptozotocin-induced diabetic rats	Restore the mitophagy [19]	
MR	Vascular smooth muscle cells	Noninfarcted mice incubated with low-dose angiotensin-II	Inhibit oxidative stress [20]	
MR	Heart	Zucker fa/fa rats	Inhibit oxidative stress [21]	
MR	Heart	Obese ZSF1 rats	Attenuate cardiac diastolic dysfunction and improve cardiac perfusion [22]	

Programmed cell death and finerenone in diabetic cardiomyopathy

In biology, cell death is broadly classified as necrosis and programmed cell death (PCD). PCD includes apoptosis [23], autophagy [23], pyroptosis [24], ferroptosis [25] and more. More and more evidence has demonstrated that PCD of cardiomyocytes is a major contributor to the development of DCM [24, 26–28]. Therefore, it is particularly important to regulate the death of cardiomyocytes in patients with diabetes cardiomyopathy. Some studies have found that finerenone can reduce cell apoptosis, restore autophagy levels and ameliorated cell pyroptosis [12, 16, 29].

Apoptosis

Apoptosis is a programmed and active death process that occurs in cells under the control of specific genes or pathways. It is carried out by proapoptotic caspases (mainly caspase-2/3/6/7/8/9/10), which cleave intracellular substrates, causing cytoplasmic contraction, chromatin concentration, nuclear dissolution, and membrane foaming, ultimately decomposing into membrane encapsulated apoptotic bodies [23]. Studies have shown that long-term hyperglycemia and excessive uptake and accumulation of free fatty acids in diabetes patients can induce cardiomyocyte apoptosis, and apoptosis promotes cardiomyocyte damage in DCM patients through a variety of signal pathways, for example, through extrinsic and intrinsic apoptotic pathways (involving caspase-3/8/9) to cause cardiomyocyte apoptosis [16, 30, 31]. And, there is an upregulation of the renin–angiotensin–aldosterone system in DCM, resulting in an increase in aldosterone levels [32, 33], and aldosterone induces cardiomyocyte apoptosis through dependence on G protein-coupled receptor-kinase (GRK) [34]. In addition, DCM can also cause vascular damage and endothelial dysfunction [30, 35].

Experiments have shown that finerenone can down-regulate the TNFa/TNFR1/CASPASE8 signaling pathway to reduce the apoptosis of cardiomyocytes [16]. And it can improve lipid metabolism in cardiomyocytes and reduce myocardial lipid uptake by down-regulating PPARγ/CD36 to indirectly improve cardiomyocyte apoptosis [16, 30, 36]. On the other hand, as a type of MRA, finerenone can block the MR of the heart, thereby blocking aldosterone induced apoptosis. GRK-5 blocks the cardiac actions of aldosterone via phosphorylation of the MR [37]. Finerenone can induce GRK-5’s phosphorylation and suppress MR basal transcriptional activity in GRK5-overexpressing cardiomyocytes (finerenone’s inverse agonism at the cardiac MR), which plays an important role in blocking cardiomyocyte apoptosis.

In an experiment on vascular injury, non-steroidal MRA finerenone prevents aldosterone-induced smooth muscle cell (SMC) proliferation and endothelial cell (EC) apoptosis [18]. Excessive activation of MR in ECs can lead to endothelial dysfunction, finerenone can block the excessive activation of MR and thus block this process [38, 39].

Autophagy

Autophagy is an intracellular degradation process that encapsulates intracellular substances into double layered membrane vesicles, forming autophagosomes that are then fused by lysosomes to degrade and recycle these substances. The autophagy process is strictly regulated by the body and is crucial for maintaining the homeostasis of the intracellular environment. But abnormal autophagy can lead to cell death [23]. According to current studies, autophagy is regulated mainly by the phosphatidylinositol 3-phosphate kinase-mamma-lian target of rapamycin (PI3K-mTOR) signal transduction pathway upstream of autophagy-associated genes (ATG) and the Beclin1 complex [23, 40]. Research has shown that DCM is closely related to inhibition of cellular autophagy [11, 28]. High fat environment will inhibit myocardial autophagy in patients with diabetes, and in high glucose environment, this autophagy inhibition will worsen [41].

Although the mechanism by which finerenone restores autophagy in cardiomyocytes is not clear, studies have shown that finerenone can attenuate mitochondrial autophagy disruption in renal tubular epithelial cells of patients with diabetes nephropathy by inhibiting MR [19], which may provide guidance.

Pyroptosis

Pyroptosis is a form of PCD that is related to the innate immune response (such as pathogen invasion), and it is usually activated by inflammatory caspases (mainly caspase-1/4/5/11) and caspase-3 and relies on Gasdermin family proteins to form membrane pores, leading to nuclear fragmentation and dissolution, increased cell membrane permeability, swelling and lysis, and release of cellular contents, thereby causing local inflammatory reactions [23, 26, 42]. Moreover, studies have found that pyroptosis is also involved in the formation of DCM [42, 43]. NLRP3 inflammasome activation of caspase-1-mediated pyroptosis plays an important role in the development of diabetic cardiomyopathy [42].

As a type of MRA, finerenone can block inflammation caused by excessive activation of MR [33]. However, whether finerenone can also inhibit NLRP3-mediated pyroptosis in cardiomyocytes remains to be verified.

Oxidative stress and finerenone in diabetic cardiomyopathy

Oxidative stress refers to the imbalance between oxidative and antioxidant effects in the body. The “redox state” is determined by the balance between production of reactive oxygen species (ROS) and their removal by the antioxidant defense system. When this balance is disrupted, excessive ROS production and/or inadequate ROS detoxification may result in ROS-induced damage to DNA, proteins, lipids and micro RNA, leading to irreversible cell damage and death [44, 45]. Meanwhile, studies have shown that reactive nitrogen species (RNS) are also involved in oxidative stress [46, 47].

Oxidative stress is believed to play an important role in DCM. Although pathogenic factors (such as high sugar and high fat) can lead to DCM through different mechanisms, the main contribution of these pathogenic factors to DCM is oxidative stress. And oxidative stress can also mediate programmed cell death, mitochondrial dysfunction, inflammation, and so on [46–48]. Due to the abundant energy provided by mitochondria for cardiac activity, when mitochondrial function is impaired, it can have harmful effects on the heart. Multiple signaling pathways are involved in the oxidative stress of DCM [47, 49], and understanding these signaling pathways has beneficial results for antioxidant therapy. And the antioxidant mechanism is another noteworthy issue. The elimination of ROS depends on enzymes such as catalase and superoxide dismutase (SOD) [12]. The MRA, finerenone, can effectively block oxidative stress induced by aldosterone, thereby protecting the heart [17].

Mitochondrial dysfunction

As the energy factory of cells, mitochondria play an important role in the sustained functioning of cells, and mitochondrial dysfunction is closely related to DCM [50]. The heart is an organ with high energy requirements, and most of the ATP it consumes comes from the oxidative metabolism of mitochondria. Mitochondria in the heart account for one-third of the volume of adult cardiomyocytes [51]. Therefore, the heart is greatly affected by mitochondrial dysfunction.

Mitochondria, as producers of intracellular energy, are also the main targets of oxidative stress. There are multiple main sources of ROS production in cardiomyocytes. However, mitochondrial sources of ROS are thought to represent the major ROS burden in the context of diabetes [44]. Persistent hyperglycemia can lead to excessive production of ROS by cardiomyocytes [52]. Increased mitochondrial ROS induce oxidative damage to DNA, proteins and lipids, and may trigger a variety of pathological pathways involved in mitochondrial and cellular damage [53, 54].

In recent years, many studies have shown that oxidative stress can affect mitochondrial function through various factors such as affecting calcium ion levels, mitochondrial membrane potential, and respiratory chain complexes [53, 55–57]. When cardiomyocytes are subjected to oxidative stress, the concentration of calcium ions in mitochondria increases, thus inhibiting the generation of mitochondrial ATP [55]. Mitochondrial dysfunction can lead to the generation of ROS, forming a "vicious cycle" of enhanced oxidative stress.

Signaling pathway of finerenone in oxidative stress

Finerenone has certain antioxidant potential. Research has shown that finerenone abrogated oxidative stress in vascular smooth muscle cells from noninfarcted mice incubated with low-dose angiotensin-II [20]. It was also found that finerenone reduced the production of myocardial ROS after short-term administration in Zucker fa/fa rats (a rat model of metabolic syndrome) [21]. In general, finerenone can exert certain benefits in cardiac protection by inhibiting oxidative stress. The analysis of the signaling pathway of finerenone in oxidative stress helps to deepen the understanding of the drug's mechanism of action, thus providing a basis for the formulation of disease treatment strategies.

In rat kidney fibroblast cells, activation of MR induces mitochondrial dysfunction through the PI3K/Akt/eNOS pathway. PI3K phosphorylation stimulates its downstream protein Akt, phosphorylates Akt (p-Akt) and eNOS, regulating a variety of physiological functions, triggering mitochondrial dysfunction. Finerenone normalizes mitochondrial dysfunction by blocking MR, ultimately reducing ROS production [19]. This is helpful for studying the role of finerenone in cardiac oxidative stress.

Finerenone improves cardiomyocyte metabolism and reduces ROS generation through PPARα/CD36 pathway. A nuclear receptor, peroxisome proliferator-activated receptor alpha (PPARα), plays an important role in myocardial substrate metabolism by regulating the transcription of genes involved in FA transport, esterification, and oxidation [47, 58]. Due to insulin resistance or lack of insulin in DCM, the uptake and utilization of glucose in cardiomyocytes are limited, and the expression of CD36 (FFA translocatase) in cardiomyocytes is increased [16], which mediates the entry of FFA into cells, thus activating PPARα, which will promote the β-oxidation (β-ox) of FFA in mitochondria, and thus promote the production of ROS [59–61]. The ROS and the expression of PPARγ and CD36 decreased after finerenone treatment, thus effectively blocking oxidative stress [16]. MR activation contributes to aldosterone-mediated activation of NADPH oxidase mediated generation of ROS in the heart and coronary microvascular [62]. Finerenone inhibits this process by blocking MR.

Intestinal microbiota and finerenone in diabetic cardiomyopathy

Maintaining a healthy microbiota in the gut is crucial for maintaining homeostasis. However, when intestinal microbial homeostasis is disrupted, it can induce the development of different diseases [63]. Intestinal microbiota and its metabolites can affect the development of diabetic cardiomyopathy by regulating oxidative stress [64], inflammation [65], insulin resistance [66], apoptosis [67], and autophagy [67, 68]. At present, the relationship between finerenone and intestinal microbiota is not clear, and the specific mechanism needs to be more thoroughly investigated.

MicroRNAs (miRNAs) and finerenone in diabetic cardiomyopathy

MicroRNAs (miRNAs) are a type of noncoding RNAs (ncRNAs) that are approximately 22-nucleotide (nt) long and are encoded by endogenous genes. MiRNAs participate in transcriptional or posttranscriptional regulation by binding to the untranslated regions of target mRNAs, thus participating in the regulation of human pathophysiological processes [14]. Based on previous studies it was found that more than 300 different miRNAs play a role in DCM [69]. For example, experiments have shown that miRNA-373 can participate in the mitogen-activated protein kinase (MAPK) mediated signaling pathway, playing an important role in cardiomyocytes hypertrophy by targeting the hypertrophic protein, MEF2C [70]. MiRNA-503 was involved in the progress of apoptosis in DCM via regulating Nrf2/ARE signaling pathway [71].And miRNA-30c can participate in the PPARα mediated signaling pathway, regulating cardiac oxidative stress by targeting peroxisome proliferator-activated receptor coactivator 1β (PGC-1β) [72]. Therefore, targeting a particular miRNA involved in a specific signaling pathway in the diabetic heart may provide a therapeutic effect to ameliorate diabetic cardiomyopathy. Finerenone can play a certain role in DCM through PPARγ/CD36 pathway [16]. Therefore, it remains to be further confirmed whether there is any relationship between it and miRNA-30c or other miRNAs.

Therapeutic applications and limitations of finerenone in diabetic cardiomyopathy

The data from clinical trials with finerenone has expanded the treatment options for cardiorenal disease management for patients with T2DM (Table 2). The results of the two major studies, FIDELIO-DKD and FIGARO-DKD, are mutually validated, and it is believed that finerenone can improve renal and cardiovascular outcomes, bringing more benefits to patients [15, 73, 74]. Although finerenone has shown positive effects in cardiorenal protection, it may also be accompanied by some side effects. Common side effects include hyperkalemia, headache, nausea, diarrhea and so on. In addition, some patients may experience adverse reactions such as hypoglycemia, and allergies [73–75]. Therefore, when using finerenone for disease treatment, it is necessary to pay attention to monitoring the patient's blood pressure and electrolyte levels, and closely observe the patient's condition.Table 2 Effect of finerenone in clinical treatment

Type	Object	Follow-up period	Effect of outcome	
Clinical trial (FIDELIO-DKD)	5674 patients with type 2 diabetes with CKD	Median follow-up of 2.6 years	Reduce risks of CKD progression and cardiovascular events [73]	
Clinical trial (FIGARO-DKD)	7352 patients with CKD and type 2 diabetes	Median follow-up of 3.4 years	Improve cardiovascular outcomes [74]	
Randomized, double-blind trial (ARTS Part B)	392 patients with HFrEF and moderate CKD	29 ± 2 days	Decrease the levels of B-type natriuretic peptide, amino-terminal proBNP, and albuminuria; have lower incidences of hyperkalaemia and worsening renal function than spironolactone [75]	
Randomized, double-blind trial (ARTS-HF)	1066 patients with worsening chronic heart failure and diabetes mellitus and/or CKD	90 days	Induce a 30% or greater decrease in NT-proBNP levels in a similar proportion of patients to eplerenone [77]	
Meta-analysis	51,496 patients with type 2 diabetes and CKD	Ranged from 90 days to 4 years	Reduce the risk of major adverse cardiovascular events, renal outcome and hospitalization for heart failure [78]	

In summary, finerenone is a novel and promising therapeutic drug for patients with chronic kidney disease (CKD), which has received regulatory approval with the indication of cardiorenal protection in patients with CKD associated with type 2 diabetes [76]. And, its indications include cardiovascular related benefits (reducing the risk of cardiovascular death and hospitalization due to heart failure). Although it has not yet been approved for use in DCM, with the expansion of new indications and continuous accumulation of clinical practice in China, finerenone may have broad clinical application prospects in the fields of CKD and chronic cardiovascular disease (CVD).

Conclusions and perspectives

Current studies indicate that finerenone can play an important role in cardiorenal protection. Compared with the first and second generation steroid MRA, the third generation non-steroidal MRA has higher affinity and selectivity for MR, and fewer side effects. A large number of experiments have shown that finerenone can inhibit the overactivation of MR. It can effectively block programmed cell death in the heart, including inhibiting cardiomyocyte apoptosis through the TNFa/TNFR1/CASPASE8 signaling pathway or downregulating PPARγ/CD36 and restoring autophagy in cardiomyocytes. Moreover, finerenone can inhibit oxidative stress, which reduces ROS production through the PPARα/CD36 pathway and inhibition of aldosterone mediated activation of NADPH oxidase (Fig. 1 By Figdraw). At the same time, finerenone can effectively anti-inflammatory and reduce vascular injury. These will lead to a certain therapeutic effect of finerenone in DCM patients (Fig. 2 By Figdraw), but it is also necessary to be alert to its possible side effects. It is worth noting that currently, intestinal microbiota and miRNAs have become relevant factors for the onset of DCM, but further experimental research is needed to investigate the relationship between finerenone and the above two. At the same time, the mechanism of action of finerenone in DCM is not fully understood. Through continuous research in the future, it is expected to become an innovative therapeutic drug in the field of CVD.Fig. 1 Related signaling pathways of finerenone in DCM

Fig. 2 Potential protective effects of finerenone in DCM

Abbreviations

MR Mineralocorticoid receptor

MRAs Mineralocorticoid receptor antagonists

DCM Diabetic cardiomyopathy

miRNAs MicroRNAs

ROS Reactive oxygen species

RNS Reactive nitrogen species

PCD Programmed cell death

GRK G protein-coupled receptor-kinase

TNFa Tumor necrosis factor alpha

PPAR Peroxisome proliferators-activated receptors

FFA Free fatty acids

SMC Smooth muscle cell

EC Endothelial cell

ATG Autophagy-associated genes

SOD Superoxide dismutase

β-ox β-Oxidation

ncRNA Noncoding RNAs

PGC-1β Peroxisome proliferator-activated receptor coactivator 1β

CKD Chronic kidney disease

CVD Cardiovascular disease

CytC Cytochrome C

Apaf-1 Apoptotic protease activating factor-1

Aldo Aldosterone

Author contributions

JW, HX, and JH conceived, designed, and planned the manuscript. JW, HX, and JH collected and read the literature. JW drafted the manuscript and prepared Figs. 1, 2. LD made extensive revisions to the manuscript during the revision process. JT analyzed the data. JF and YJ conceived, designed, and revised the manuscript. All authors read and approved the final manuscript.

Funding

This research was funded by grants from Sichuan Science and Technology Program (2022YFS0610), Luzhou Municipal People’s Government—Southwest Medical University Science and Technology Strategic Cooperation (2021LZXNYD-J33), Hejiang County People's Hospital—Southwest Medical University Science and Technology Strategic Cooperation Project (2021HJXNYD13, 2021HJXNYD04 and 2022HJXNYD05), Xuyong County People’s Hospital—Southwest Medical University Science and Technology Strategic Cooperation Project (2024XYXNYD18) and Gulin County People's Hospital—Affiliated Hospital of Southwest Medical University Science and Technology strategic Cooperation (2022GLXNYDFY13), 2022-N-01-33 project of China International Medical Foundation, Provincial-level science and Technology Program Transfer Payment Special Fund project of Panzhihua Science and Technology Bureau (222ZYZF-S-01).

Availability of data and materials

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Competing interests

The authors declare no competing interests.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Jing Wang, Haojie Xue and Jinyu He contributed equally to this work.
==== Refs
References

1. Goenka L Padmanaban R George M The ascent of mineralocorticoid receptor antagonists in diabetic nephropathy Curr Clin Pharmacol 2019 14 2 78 83 10.2174/1574884713666181116100946 30444201
Goenka L, Padmanaban R, George M. The ascent of mineralocorticoid receptor antagonists in diabetic nephropathy. Curr Clin Pharmacol. 2019;14(2):78–83.30444201
2. Crompton M Skinner LJ Satchell SC Aldosterone: essential for life but damaging to the vascular endothelium Biomolecules 2023 13 6 1004 10.3390/biom13061004 37371584
Crompton M, Skinner LJ, Satchell SC, et al. Aldosterone: essential for life but damaging to the vascular endothelium. Biomolecules. 2023;13(6):1004.37371584
3. Tsujimoto T Kajio H Spironolactone use and improved outcomes in patients with heart failure with preserved ejection fraction with resistant hypertension J Am Heart Assoc 2020 9 23 e018827 10.1161/JAHA.120.018827 33222584
Tsujimoto T, Kajio H. Spironolactone use and improved outcomes in patients with heart failure with preserved ejection fraction with resistant hypertension. J Am Heart Assoc. 2020;9(23):e018827.33222584
4. Kolkhof P Lawatscheck R Filippatos G Nonsteroidal mineralocorticoid receptor antagonism by finerenone—translational aspects and clinical perspectives across multiple organ systems Int J Mol Sci 2022 23 16 9243 10.3390/ijms23169243 36012508
Kolkhof P, Lawatscheck R, Filippatos G, et al. Nonsteroidal mineralocorticoid receptor antagonism by finerenone—translational aspects and clinical perspectives across multiple organ systems. Int J Mol Sci. 2022;23(16):9243.36012508
5. Gregg LP Navaneethan SD Steroidal or non-steroidal MRAs: should we still enable RAASi use through K binders? Nephrol Dial Transplant 2023 38 6 1355 1365 10.1093/ndt/gfac284 36264349
Gregg LP, Navaneethan SD. Steroidal or non-steroidal MRAs: should we still enable RAASi use through K binders? Nephrol Dial Transplant. 2023;38(6):1355–65.36264349
6. Secora AM Shin J-I Qiao Y Hyperkalemia and acute kidney injury with spironolactone use among patients with heart failure Mayo Clin Proc 2020 95 11 2408 2419 10.1016/j.mayocp.2020.03.035 33153631
Secora AM, Shin J-I, Qiao Y, et al. Hyperkalemia and acute kidney injury with spironolactone use among patients with heart failure. Mayo Clin Proc. 2020;95(11):2408–19.33153631
7. Naser N Nalbantic A Nalbantic N The effectiveness of eplerenone vs spironolactone on left ventricular systolic function, hospitalization and cardiovascular death in patients with chronic heart failure—HFrEF Med Arch 2023 77 2 105 10.5455/medarh.2023.77.105-111 37260796
Naser N, Nalbantic A, Nalbantic N, et al. The effectiveness of eplerenone vs spironolactone on left ventricular systolic function, hospitalization and cardiovascular death in patients with chronic heart failure—HFrEF. Med Arch. 2023;77(2):105.37260796
8. Kintscher U Edelmann F The non-steroidal mineralocorticoid receptor antagonist finerenone and heart failure with preserved ejection fraction Cardiovasc Diabetol 2023 22 1 162 10.1186/s12933-023-01899-0 37386461
Kintscher U, Edelmann F. The non-steroidal mineralocorticoid receptor antagonist finerenone and heart failure with preserved ejection fraction. Cardiovasc Diabetol. 2023;22(1):162.37386461
9. Agarwal R Kolkhof P Bakris G Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine Eur Heart J 2021 42 2 152 161 10.1093/eurheartj/ehaa736 33099609
Agarwal R, Kolkhof P, Bakris G, et al. Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine. Eur Heart J. 2021;42(2):152–61.33099609
10. Graczyk P Dach A Dyrka K Pathophysiology and advances in the therapy of cardiomyopathy in patients with diabetes mellitus Int J Mol Sci 2024 25 9 5027 10.3390/ijms25095027 38732253
Graczyk P, Dach A, Dyrka K, et al. Pathophysiology and advances in the therapy of cardiomyopathy in patients with diabetes mellitus. Int J Mol Sci. 2024;25(9):5027.38732253
11. Qiao S Hong L Zhu Y RIPK1-RIPK3 mediates myocardial fibrosis in type 2 diabetes mellitus by impairing autophagic flux of cardiac fibroblasts Cell Death Disease 2022 13 2 147 10.1038/s41419-022-04587-1 35165268
Qiao S, Hong L, Zhu Y, et al. RIPK1-RIPK3 mediates myocardial fibrosis in type 2 diabetes mellitus by impairing autophagic flux of cardiac fibroblasts. Cell Death Disease. 2022;13(2):147.35165268
12. Theofilis P Vordoni A Kalaitzidis RG Oxidative stress management in cardiorenal diseases: focus on novel antidiabetic agents, finerenone, and melatonin Life 2022 12 10 1663 10.3390/life12101663 36295098
Theofilis P, Vordoni A, Kalaitzidis RG. Oxidative stress management in cardiorenal diseases: focus on novel antidiabetic agents, finerenone, and melatonin. Life. 2022;12(10):1663.36295098
13. Yang Y Zhao M He X Pyridostigmine protects against diabetic cardiomyopathy by regulating vagal activity, gut microbiota, and branched-chain amino acid catabolism in diabetic mice Front Pharmacol 2021 12 647481 10.3389/fphar.2021.647481 34084135
Yang Y, Zhao M, He X, et al. Pyridostigmine protects against diabetic cardiomyopathy by regulating vagal activity, gut microbiota, and branched-chain amino acid catabolism in diabetic mice. Front Pharmacol. 2021;12:647481.34084135
14. He X Kuang G Wu Y Emerging roles of exosomal miRNAs in diabetes mellitus Clin Transl Med 2021 11 6 e468 10.1002/ctm2.468 34185424
He X, Kuang G, Wu Y, et al. Emerging roles of exosomal miRNAs in diabetes mellitus. Clin Transl Med. 2021;11(6):e468.34185424
15. Palanisamy S Funes Hernandez M Chang TI Cardiovascular and renal outcomes with finerenone, a selective mineralocorticoid receptor antagonist Cardiol Thera 2022 11 3 337 354 10.1007/s40119-022-00269-3
Palanisamy S, Funes Hernandez M, Chang TI, et al. Cardiovascular and renal outcomes with finerenone, a selective mineralocorticoid receptor antagonist. Cardiol Thera. 2022;11(3):337–54.
16. Jin T Fu X Liu M Finerenone attenuates myocardial apoptosis, metabolic disturbance and myocardial fibrosis in type 2 diabetes mellitus Diabetol Metab Syndr 2023 15 1 87 10.1186/s13098-023-01064-3 37120554
Jin T, Fu X, Liu M, et al. Finerenone attenuates myocardial apoptosis, metabolic disturbance and myocardial fibrosis in type 2 diabetes mellitus. Diabetol Metab Syndr. 2023;15(1):87.37120554
17. Pollard CM Suster MS Cora N GRK5 is an essential co-repressor of the cardiac mineralocorticoid receptor and is selectively induced by finerenone World J Cardiol 2022 14 4 220 230 10.4330/wjc.v14.i4.220 35582468
Pollard CM, Suster MS, Cora N, et al. GRK5 is an essential co-repressor of the cardiac mineralocorticoid receptor and is selectively induced by finerenone. World J Cardiol. 2022;14(4):220–30.35582468
18. Alvarez de la Rosa D Dutzmann J Musmann R-J The novel mineralocorticoid receptor antagonist finerenone attenuates neointima formation after vascular injury PLoS ONE 2017 12 9 e0184888 10.1371/journal.pone.0184888 28926607
Alvarez de la Rosa D, Dutzmann J, Musmann R-J, et al. The novel mineralocorticoid receptor antagonist finerenone attenuates neointima formation after vascular injury. PLoS ONE. 2017;12(9):e0184888.28926607
19. Yao L Liang X Liu Y Non-steroidal mineralocorticoid receptor antagonist finerenone ameliorates mitochondrial dysfunction via PI3K/Akt/eNOS signaling pathway in diabetic tubulopathy Redox Biol 2023 68 102946 10.1016/j.redox.2023.102946 37924663
Yao L, Liang X, Liu Y, et al. Non-steroidal mineralocorticoid receptor antagonist finerenone ameliorates mitochondrial dysfunction via PI3K/Akt/eNOS signaling pathway in diabetic tubulopathy. Redox Biol. 2023;68: 102946.37924663
20. Gueret A Harouki N Favre J Vascular smooth muscle mineralocorticoid receptor contributes to coronary and left ventricular dysfunction after myocardial infarction Hypertension (Dallas, Tex: 1979) 2016 67 4 717 723 10.1161/HYPERTENSIONAHA.115.06709 26902493
Gueret A, Harouki N, Favre J, et al. Vascular smooth muscle mineralocorticoid receptor contributes to coronary and left ventricular dysfunction after myocardial infarction. Hypertension (Dallas, Tex: 1979). 2016;67(4):717–23.26902493
21. Lachaux M Barrera-Chimal J Nicol L Short- and long-term administration of the non-steroidal mineralocorticoid receptor antagonist finerenone opposes metabolic syndrome-related cardio-renal dysfunction Diabetes Obes Metab 2018 20 10 2399 2407 10.1111/dom.13393 29862614
Lachaux M, Barrera-Chimal J, Nicol L, et al. Short- and long-term administration of the non-steroidal mineralocorticoid receptor antagonist finerenone opposes metabolic syndrome-related cardio-renal dysfunction. Diabetes Obes Metab. 2018;20(10):2399–407.29862614
22. Lima-Posada I Stephan Y Soulié M Benefits of the non-steroidal mineralocorticoid receptor antagonist finerenone in metabolic syndrome-related heart failure with preserved ejection fraction Int J Mol Sci 2023 24 3 2536 10.3390/ijms24032536 36768859
Lima-Posada I, Stephan Y, Soulié M, et al. Benefits of the non-steroidal mineralocorticoid receptor antagonist finerenone in metabolic syndrome-related heart failure with preserved ejection fraction. Int J Mol Sci. 2023;24(3):2536.36768859
23. Chen Y Li X Yang M Research progress on morphology and mechanism of programmed cell death Cell Death Disease 2024 15 5 327 10.1038/s41419-024-06712-8 38729953
Chen Y, Li X, Yang M, et al. Research progress on morphology and mechanism of programmed cell death. Cell Death Disease. 2024;15(5):327.38729953
24. Liu Z Chen Y Mei Y Gasdermin d-mediated pyroptosis in diabetic cardiomyopathy: molecular mechanisms and pharmacological implications Molecules 2023 28 23 7813 10.3390/molecules28237813 38067543
Liu Z, Chen Y, Mei Y, et al. Gasdermin d-mediated pyroptosis in diabetic cardiomyopathy: molecular mechanisms and pharmacological implications. Molecules. 2023;28(23):7813.38067543
25. Xie D Li K Feng R Ferroptosis and traditional chinese medicine for type 2 diabetes mellitus Diabetes Metab Syndr Obes 2023 16 1915 1930 10.2147/DMSO.S412747 37398945
Xie D, Li K, Feng R, et al. Ferroptosis and traditional chinese medicine for type 2 diabetes mellitus. Diabetes Metab Syndr Obes. 2023;16:1915–30.37398945
26. Wei Y Yang L Pandeya A Pyroptosis-induced inflammation and tissue damage J Mol Biol 2022 434 4 167301 10.1016/j.jmb.2021.167301 34653436
Wei Y, Yang L, Pandeya A, et al. Pyroptosis-induced inflammation and tissue damage. J Mol Biol. 2022;434(4):167301.34653436
27. Altamimi JZ Alfaris NA Alshammari GM Esculeoside A decreases diabetic cardiomyopathy in streptozotocin-treated rats by attenuating oxidative stress, inflammation, fibrosis, and apoptosis: impressive role of Nrf2 Medicina 2023 59 10 1830 10.3390/medicina59101830 37893548
Altamimi JZ, Alfaris NA, Alshammari GM, et al. Esculeoside A decreases diabetic cardiomyopathy in streptozotocin-treated rats by attenuating oxidative stress, inflammation, fibrosis, and apoptosis: impressive role of Nrf2. Medicina. 2023;59(10):1830.37893548
28. You P Chen H Han W miR-200a-3p overexpression alleviates diabetic cardiomyopathy injury in mice by regulating autophagy through the FOXO3/Mst1/Sirt3/AMPK axis PeerJ 2023 11 e15840 10.7717/peerj.15840 37727684
You P, Chen H, Han W, et al. miR-200a-3p overexpression alleviates diabetic cardiomyopathy injury in mice by regulating autophagy through the FOXO3/Mst1/Sirt3/AMPK axis. PeerJ. 2023;11:e15840.37727684
29. di Lullo L Lavalle C Scatena A Finerenone: questions and answers—the four fundamental arguments on the new-born promising non-steroidal mineralocorticoid receptor antagonist J Clin Med 2023 12 12 3992 10.3390/jcm12123992 37373685
di Lullo L, Lavalle C, Scatena A, et al. Finerenone: questions and answers—the four fundamental arguments on the new-born promising non-steroidal mineralocorticoid receptor antagonist. J Clin Med. 2023;12(12):3992.37373685
30. Chen Y Hua Y Li X Distinct types of cell death and the implication in diabetic cardiomyopathy Front Pharmacol 2020 11 42 10.3389/fphar.2020.00042 32116717
Chen Y, Hua Y, Li X, et al. Distinct types of cell death and the implication in diabetic cardiomyopathy. Front Pharmacol. 2020;11:42.32116717
31. Sun S Yang S Dai M The effect of Astragalus polysaccharides on attenuation of diabetic cardiomyopathy through inhibiting the extrinsic and intrinsic apoptotic pathways in high glucose -stimulated H9C2 cells BMC Complement Altern Med 2017 17 1 310 10.1186/s12906-017-1828-7 28610566
Sun S, Yang S, Dai M, et al. The effect of Astragalus polysaccharides on attenuation of diabetic cardiomyopathy through inhibiting the extrinsic and intrinsic apoptotic pathways in high glucose -stimulated H9C2 cells. BMC Complement Altern Med. 2017;17(1):310.28610566
32. Grubićrotkvić P Planinić Z Liberatipršo A-M The mystery of diabetic cardiomyopathy: from early concepts and underlying mechanisms to novel therapeutic possibilities Int J Mol Sci 2021 22 11 5973 10.3390/ijms22115973 34205870
Grubićrotkvić P, Planinić Z, Liberatipršo A-M, et al. The mystery of diabetic cardiomyopathy: from early concepts and underlying mechanisms to novel therapeutic possibilities. Int J Mol Sci. 2021;22(11):5973.34205870
33. Bernardi S Michelli A Zuolo G Update on RAAS modulation for the treatment of diabetic cardiovascular disease J Diabetes Res 2016 2016 1 17 10.1155/2016/8917578
Bernardi S, Michelli A, Zuolo G, et al. Update on RAAS modulation for the treatment of diabetic cardiovascular disease. J Diabetes Res. 2016;2016:1–17.
34. Cannavo A Liccardo D Eguchi A Myocardial pathology induced by aldosterone is dependent on non-canonical activities of G protein-coupled receptor kinases Nat Commun 2016 7 1 10877 10.1038/ncomms10877 26932512
Cannavo A, Liccardo D, Eguchi A, et al. Myocardial pathology induced by aldosterone is dependent on non-canonical activities of G protein-coupled receptor kinases. Nat Commun. 2016;7(1):10877.26932512
35. Shi X Liu C Chen J Endothelial MICU1 alleviates diabetic cardiomyopathy by attenuating nitrative stress-mediated cardiac microvascular injury Cardiovasc Diabetol 2023 22 1 216 10.1186/s12933-023-01941-1 37592255
Shi X, Liu C, Chen J, et al. Endothelial MICU1 alleviates diabetic cardiomyopathy by attenuating nitrative stress-mediated cardiac microvascular injury. Cardiovasc Diabetol. 2023;22(1):216.37592255
36. Morse PT Arroum T Wan J Phosphorylations and acetylations of cytochrome c control mitochondrial respiration, mitochondrial membrane potential, energy, ROS, and apoptosis Cells 2024 13 6 493 10.3390/cells13060493 38534337
Morse PT, Arroum T, Wan J, et al. Phosphorylations and acetylations of cytochrome c control mitochondrial respiration, mitochondrial membrane potential, energy, ROS, and apoptosis. Cells. 2024;13(6):493.38534337
37. Maning J McCrink K Pollard C Antagonistic roles of GRK2 and GRK5 in cardiac aldosterone signaling reveal GRK5-mediated cardioprotection via mineralocorticoid receptor inhibition Int J Mol Sci 2020 21 8 2868 10.3390/ijms21082868 32326036
Maning J, McCrink K, Pollard C, et al. Antagonistic roles of GRK2 and GRK5 in cardiac aldosterone signaling reveal GRK5-mediated cardioprotection via mineralocorticoid receptor inhibition. Int J Mol Sci. 2020;21(8):2868.32326036
38. Moss ME Carvajal B Jaffe IZ The endothelial mineralocorticoid receptor: contributions to sex differences in cardiovascular disease Pharmacol Therapeut 2019 203 107387 10.1016/j.pharmthera.2019.06.009
Moss ME, Carvajal B, Jaffe IZ. The endothelial mineralocorticoid receptor: contributions to sex differences in cardiovascular disease. Pharmacol Therapeut. 2019;203:107387.
39. Lv R Xu L Che L Cardiovascular-renal protective effect and molecular mechanism of finerenone in type 2 diabetic mellitus Front Endocrinol 2023 14 1125693 10.3389/fendo.2023.1125693
Lv R, Xu L, Che L, et al. Cardiovascular-renal protective effect and molecular mechanism of finerenone in type 2 diabetic mellitus. Front Endocrinol. 2023;14:1125693.
40. Wang H Wang L Hu F Neuregulin-4 attenuates diabetic cardiomyopathy by regulating autophagy via the AMPK/mTOR signalling pathway Cardiovasc Diabetol 2022 21 1 205 10.1186/s12933-022-01643-0 36221104
Wang H, Wang L, Hu F, et al. Neuregulin-4 attenuates diabetic cardiomyopathy by regulating autophagy via the AMPK/mTOR signalling pathway. Cardiovasc Diabetol. 2022;21(1):205.36221104
41. Zang H Wu W Qi L Autophagy inhibition enables Nrf2 to exaggerate the progression of diabetic cardiomyopathy in mice Diabetes 2020 69 12 2720 2734 10.2337/db19-1176 32948607
Zang H, Wu W, Qi L, et al. Autophagy inhibition enables Nrf2 to exaggerate the progression of diabetic cardiomyopathy in mice. Diabetes. 2020;69(12):2720–34.32948607
42. Ji N Qi Z Wang Y Pyroptosis: a new regulating mechanism in cardiovascular disease J Inflamm Res 2021 14 2647 2666 10.2147/JIR.S308177 34188515
Ji N, Qi Z, Wang Y, et al. Pyroptosis: a new regulating mechanism in cardiovascular disease. J Inflamm Res. 2021;14:2647–66.34188515
43. Lu Y Lu Y Meng J Pyroptosis and its regulation in diabetic cardiomyopathy Front Physiol 2022 12 791848 10.3389/fphys.2021.791848 35145423
Lu Y, Lu Y, Meng J, et al. Pyroptosis and its regulation in diabetic cardiomyopathy. Front Physiol. 2022;12:791848.35145423
44. Byrne NJ Rajasekaran NS Abel ED Therapeutic potential of targeting oxidative stress in diabetic cardiomyopathy Free Radical Biol Med 2021 169 317 342 10.1016/j.freeradbiomed.2021.03.046 33910093
Byrne NJ, Rajasekaran NS, Abel ED, et al. Therapeutic potential of targeting oxidative stress in diabetic cardiomyopathy. Free Radical Biol Med. 2021;169:317–42.33910093
45. de Geest B Mishra M Role of oxidative stress in diabetic cardiomyopathy Antioxidants 2022 11 4 784 10.3390/antiox11040784 35453469
de Geest B, Mishra M. Role of oxidative stress in diabetic cardiomyopathy. Antioxidants. 2022;11(4):784.35453469
46. Liu Q Wang S Cai L Diabetic cardiomyopathy and its mechanisms: role of oxidative stress and damage J Diabetes Investig 2014 5 6 623 634 10.1111/jdi.12250 25422760
Liu Q, Wang S, Cai L. Diabetic cardiomyopathy and its mechanisms: role of oxidative stress and damage. J Diabetes Investig. 2014;5(6):623–34.25422760
47. Peng ML Fu Y Wu CW Signaling pathways related to oxidative stress in diabetic cardiomyopathy Front Endocrinol (Lausanne) 2022 13 907757 10.3389/fendo.2022.907757 35784531
Peng ML, Fu Y, Wu CW, et al. Signaling pathways related to oxidative stress in diabetic cardiomyopathy. Front Endocrinol (Lausanne). 2022;13: 907757.35784531
48. Sapian S Taib IS Latip J Therapeutic approach of flavonoid in ameliorating diabetic cardiomyopathy by targeting mitochondrial-induced oxidative stress Int J Mol Sci 2021 22 21 11616 10.3390/ijms222111616 34769045
Sapian S, Taib IS, Latip J, et al. Therapeutic approach of flavonoid in ameliorating diabetic cardiomyopathy by targeting mitochondrial-induced oxidative stress. Int J Mol Sci. 2021;22(21):11616.34769045
49. Watanabe K Thandavarayan RA Harima M Role of differential signaling pathways and oxidative stress in diabetic cardiomyopathy Curr Cardiol Rev 2010 6 280 290 10.2174/157340310793566145 22043204
Watanabe K, Thandavarayan RA, Harima M, et al. Role of differential signaling pathways and oxidative stress in diabetic cardiomyopathy. Curr Cardiol Rev. 2010;6:280–90.22043204
50. Jubaidi FF Zainalabidin S Mariappan V Mitochondrial dysfunction in diabetic cardiomyopathy: the possible therapeutic roles of phenolic acids Int J Mol Sci 2020 21 17 6043 10.3390/ijms21176043 32842567
Jubaidi FF, Zainalabidin S, Mariappan V, et al. Mitochondrial dysfunction in diabetic cardiomyopathy: the possible therapeutic roles of phenolic acids. Int J Mol Sci. 2020;21(17):6043.32842567
51. Zhou B Tian R Mitochondrial dysfunction in pathophysiology of heart failure J Clin Investig 2018 128 9 3716 3726 10.1172/JCI120849 30124471
Zhou B, Tian R. Mitochondrial dysfunction in pathophysiology of heart failure. J Clin Investig. 2018;128(9):3716–26.30124471
52. Hamblin M Friedman DB Hill S Alterations in the diabetic myocardial proteome coupled with increased myocardial oxidative stress underlies diabetic cardiomyopathy J Mol Cell Cardiol 2007 42 4 884 895 10.1016/j.yjmcc.2006.12.018 17320100
Hamblin M, Friedman DB, Hill S, et al. Alterations in the diabetic myocardial proteome coupled with increased myocardial oxidative stress underlies diabetic cardiomyopathy. J Mol Cell Cardiol. 2007;42(4):884–95.17320100
53. Gollmer J Zirlik A Bugger H Mitochondrial mechanisms in diabetic cardiomyopathy Diabetes Metab J 2020 44 1 33 10.4093/dmj.2019.0185 32097997
Gollmer J, Zirlik A, Bugger H. Mitochondrial mechanisms in diabetic cardiomyopathy. Diabetes Metab J. 2020;44(1):33.32097997
54. Jubaidi FF Zainalabidin S Taib IS The potential role of flavonoids in ameliorating diabetic cardiomyopathy via alleviation of cardiac oxidative stress, inflammation and apoptosis Int J Mol Sci 2021 22 10 5094 10.3390/ijms22105094 34065781
Jubaidi FF, Zainalabidin S, Taib IS, et al. The potential role of flavonoids in ameliorating diabetic cardiomyopathy via alleviation of cardiac oxidative stress, inflammation and apoptosis. Int J Mol Sci. 2021;22(10):5094.34065781
55. Jaquenod de Giusti C Palomeque J Mattiazzi A Ca2+ mishandling and mitochondrial dysfunction: a converging road to prediabetic and diabetic cardiomyopathy Pflügers Arch Eur J Physiol 2022 474 1 33 61 10.1007/s00424-021-02650-y 34978597
Jaquenod de Giusti C, Palomeque J, Mattiazzi A. Ca2+ mishandling and mitochondrial dysfunction: a converging road to prediabetic and diabetic cardiomyopathy. Pflügers Arch Eur J Physiol. 2022;474(1):33–61.34978597
56. Galloway CA Yoon Y Mitochondrial dynamics in diabetic cardiomyopathy Antioxid Redox Signal 2015 22 17 1545 1562 10.1089/ars.2015.6293 25738230
Galloway CA, Yoon Y. Mitochondrial dynamics in diabetic cardiomyopathy. Antioxid Redox Signal. 2015;22(17):1545–62.25738230
57. Cai C Wu F He J Mitochondrial quality control in diabetic cardiomyopathy: from molecular mechanisms to therapeutic strategies Int J Biol Sci 2022 18 14 5276 5290 10.7150/ijbs.75402 36147470
Cai C, Wu F, He J, et al. Mitochondrial quality control in diabetic cardiomyopathy: from molecular mechanisms to therapeutic strategies. Int J Biol Sci. 2022;18(14):5276–90.36147470
58. Wu L Wang K Wang W Glucagon-like peptide-1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway Aging Cell 2018 17 4 e12763 10.1111/acel.12763 29659121
Wu L, Wang K, Wang W, et al. Glucagon-like peptide-1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway. Aging Cell. 2018;17(4): e12763.29659121
59. Lin Y Liu R Huang Y Reactivation of PPARα alleviates myocardial lipid accumulation and cardiac dysfunction by improving fatty acid β-oxidation in Dsg2-deficient arrhythmogenic cardiomyopathy Acta Pharmaceut Sin B 2023 13 1 192 203 10.1016/j.apsb.2022.05.018
Lin Y, Liu R, Huang Y, et al. Reactivation of PPARα alleviates myocardial lipid accumulation and cardiac dysfunction by improving fatty acid β-oxidation in Dsg2-deficient arrhythmogenic cardiomyopathy. Acta Pharmaceut Sin B. 2023;13(1):192–203.
60. Son NH Yu S Tuinei J PPARγ-induced cardiolipotoxicity in mice is ameliorated by PPARα deficiency despite increases in fatty acid oxidation J Clin Investig 2010 120 10 3443 3454 10.1172/JCI40905 20852389
Son NH, Yu S, Tuinei J, et al. PPARγ-induced cardiolipotoxicity in mice is ameliorated by PPARα deficiency despite increases in fatty acid oxidation. J Clin Investig. 2010;120(10):3443–54.20852389
61. Cortassa S Sollott SJ Aon MA Mitochondrial respiration and ROS emission during β-oxidation in the heart: an experimental-computational study PLoS Comput Biol 2017 13 6 e1005588 10.1371/journal.pcbi.1005588 28598967
Cortassa S, Sollott SJ, Aon MA. Mitochondrial respiration and ROS emission during β-oxidation in the heart: an experimental-computational study. PLoS Comput Biol. 2017;13(6): e1005588.28598967
62. Jia G Jia Y Sowers JR Role of mineralocorticoid receptor activation in cardiac diastolic dysfunction Biochim Biophys Acta (BBA) Mol Basis Disease 2017 1863 8 2012 2018 10.1016/j.bbadis.2016.10.025
Jia G, Jia Y, Sowers JR. Role of mineralocorticoid receptor activation in cardiac diastolic dysfunction. Biochim Biophys Acta (BBA) Mol Basis Disease. 2017;1863(8):2012–8.
63. Huang YL Xiang Q Zou JJ Zuogui Jiangtang Shuxin formula Ameliorates diabetic cardiomyopathy mice via modulating gut-heart axis Front Endocrinol (Lausanne) 2023 14 1106812 10.3389/fendo.2023.1106812 36843604
Huang YL, Xiang Q, Zou JJ, et al. Zuogui Jiangtang Shuxin formula Ameliorates diabetic cardiomyopathy mice via modulating gut-heart axis. Front Endocrinol (Lausanne). 2023;14:1106812.36843604
64. Sah SP Tirkey N Kuhad A Effect of quercetin on lipopolysaccharide induced-sickness behavior and oxidative stress in rats Indian J Pharmacol 2011 43 2 192 196 10.4103/0253-7613.77365 21572657
Sah SP, Tirkey N, Kuhad A, et al. Effect of quercetin on lipopolysaccharide induced-sickness behavior and oxidative stress in rats. Indian J Pharmacol. 2011;43(2):192–6.21572657
65. Sun X Jiao X Ma Y Trimethylamine N-oxide induces inflammation and endothelial dysfunction in human umbilical vein endothelial cells via activating ROS-TXNIP-NLRP3 inflammasome Biochem Biophys Res Commun 2016 481 1–2 63 70 10.1016/j.bbrc.2016.11.017 27833015
Sun X, Jiao X, Ma Y, et al. Trimethylamine N-oxide induces inflammation and endothelial dysfunction in human umbilical vein endothelial cells via activating ROS-TXNIP-NLRP3 inflammasome. Biochem Biophys Res Commun. 2016;481(1–2):63–70.27833015
66. Saad MJ Santos A Prada PO Linking gut microbiota and inflammation to obesity and insulin resistance Physiology (Bethesda) 2016 31 4 283 293 27252163
Saad MJ, Santos A, Prada PO. Linking gut microbiota and inflammation to obesity and insulin resistance. Physiology (Bethesda). 2016;31(4):283–93.27252163
67. Qiao CM Sun MF Jia XB Sodium butyrate causes α-synuclein degradation by an Atg5-dependent and PI3K/Akt/mTOR-related autophagy pathway Exp Cell Res 2020 387 1 111772 10.1016/j.yexcr.2019.111772 31836471
Qiao CM, Sun MF, Jia XB, et al. Sodium butyrate causes α-synuclein degradation by an Atg5-dependent and PI3K/Akt/mTOR-related autophagy pathway. Exp Cell Res. 2020;387(1): 111772.31836471
68. Zhao G Zhang X Wang H Beta carotene protects H9c2 cardiomyocytes from advanced glycation end product-induced endoplasmic reticulum stress, apoptosis, and autophagy via the PI3K/Akt/mTOR signaling pathway Ann Transl Med 2020 8 10 647 10.21037/atm-20-3768 32566584
Zhao G, Zhang X, Wang H, et al. Beta carotene protects H9c2 cardiomyocytes from advanced glycation end product-induced endoplasmic reticulum stress, apoptosis, and autophagy via the PI3K/Akt/mTOR signaling pathway. Ann Transl Med. 2020;8(10):647.32566584
69. Jakubik D Fitas A Eyileten C MicroRNAs and long non-coding RNAs in the pathophysiological processes of diabetic cardiomyopathy: emerging biomarkers and potential therapeutics Cardiovasc Diabetol 2021 20 1 55 10.1186/s12933-021-01245-2 33639953
Jakubik D, Fitas A, Eyileten C, et al. MicroRNAs and long non-coding RNAs in the pathophysiological processes of diabetic cardiomyopathy: emerging biomarkers and potential therapeutics. Cardiovasc Diabetol. 2021;20(1):55.33639953
70. Shen E Diao X Wang X MicroRNAs involved in the mitogen-activated protein kinase cascades pathway during glucose-induced cardiomyocyte hypertrophy Am J Pathol 2011 179 2 639 650 10.1016/j.ajpath.2011.04.034 21704010
Shen E, Diao X, Wang X, et al. MicroRNAs involved in the mitogen-activated protein kinase cascades pathway during glucose-induced cardiomyocyte hypertrophy. Am J Pathol. 2011;179(2):639–50.21704010
71. Miao Y Wan Q Liu X miR-503 is involved in the protective effect of phase II enzyme inducer (CPDT) in diabetic cardiomyopathy via Nrf2/ARE signaling pathway Biomed Res Int 2017 2017 9167450 10.1155/2017/9167450 29404371
Miao Y, Wan Q, Liu X, et al. miR-503 is involved in the protective effect of phase II enzyme inducer (CPDT) in diabetic cardiomyopathy via Nrf2/ARE signaling pathway. Biomed Res Int. 2017;2017:9167450.29404371
72. Yin Z Zhao Y He M MiR-30c/PGC-1β protects against diabetic cardiomyopathy via PPARα Cardiovasc Diabetol 2019 18 1 7 10.1186/s12933-019-0811-7 30635067
Yin Z, Zhao Y, He M, et al. MiR-30c/PGC-1β protects against diabetic cardiomyopathy via PPARα. Cardiovasc Diabetol. 2019;18(1):7.30635067
73. Bakris GL Agarwal R Anker SD Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes N Engl J Med 2020 383 23 2219 2229 10.1056/NEJMoa2025845 33264825
Bakris GL, Agarwal R, Anker SD, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020;383(23):2219–29.33264825
74. Pitt B Filippatos G Agarwal R Cardiovascular events with finerenone in kidney disease and type 2 diabetes N Engl J Med 2021 385 24 2252 2263 10.1056/NEJMoa2110956 34449181
Pitt B, Filippatos G, Agarwal R, et al. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N Engl J Med. 2021;385(24):2252–63.34449181
75. Pitt B Kober L Ponikowski P Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial Eur Heart J 2013 34 31 2453 2463 10.1093/eurheartj/eht187 23713082
Pitt B, Kober L, Ponikowski P, et al. Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial. Eur Heart J. 2013;34(31):2453–63.23713082
76. Heinig R Eissing T The pharmacokinetics of the nonsteroidal mineralocorticoid receptor antagonist finerenone Clin Pharmacokinet 2023 62 12 1673 1693 10.1007/s40262-023-01312-9 37875671
Heinig R, Eissing T. The pharmacokinetics of the nonsteroidal mineralocorticoid receptor antagonist finerenone. Clin Pharmacokinet. 2023;62(12):1673–93.37875671
77. Filippatos G Anker SD Böhm M A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease Eur Heart J 2016 37 27 2105 2114 10.1093/eurheartj/ehw132 27130705
Filippatos G, Anker SD, Böhm M, et al. A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease. Eur Heart J. 2016;37(27):2105–14.27130705
78. Zhang Y Jiang L Wang J Network meta-analysis on the effects of finerenone versus SGLT2 inhibitors and GLP-1 receptor agonists on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus and chronic kidney disease Cardiovasc Diabetol 2022 21 1 232 10.1186/s12933-022-01676-5 36335326
Zhang Y, Jiang L, Wang J, et al. Network meta-analysis on the effects of finerenone versus SGLT2 inhibitors and GLP-1 receptor agonists on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus and chronic kidney disease. Cardiovasc Diabetol. 2022;21(1):232.36335326
