
==== Front
medRxiv
MEDRXIV
medRxiv
Cold Spring Harbor Laboratory

10.1101/2024.08.19.24312277
preprint
1
Article
Endogenous adenine is a potential driver of the cardiovascular-kidney-metabolic syndrome
Tamayo Ian
Lee Hak Joo
Aslam M. Imran http://orcid.org/0000-0003-4560-8661

Liu Jian-Jun
Ragi Nagarjunachary
Karanam Varsha
Maity Soumya
Saliba Afaf
Treviño Esmeralda
Zheng Huili http://orcid.org/0000-0002-3976-0088

Lim Su Chi
Lanzer Jan D.
Bjornstad Petter
Tuttle Katherine http://orcid.org/0000-0002-2235-0103

Bedi Kenneth C.
Margulies Kenneth B.
Ramachandran Vasan
Abdel-Latif Ahmed http://orcid.org/0000-0002-8178-7102

Saez-Rodriguez Julio
Iyengar Ravi http://orcid.org/0000-0002-7814-0180

Bopassa Jean C.
Sharma Kumar http://orcid.org/0000-0002-7550-8525

20 8 2024
2024.08.19.24312277https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://medrxiv.org/lookup/doi/10.1101/2024.08.19.24312277
nihpp-2024.08.19.24312277.pdf
Abstract

Mechanisms underlying the cardiovascular-kidney-metabolic (CKM) syndrome are unknown, although key small molecule metabolites may be involved. Bulk and spatial metabolomics identified adenine to be upregulated and specifically enriched in coronary blood vessels in hearts from patients with diabetes and left ventricular hypertrophy. Single nucleus gene expression studies revealed that endothelial methylthioadenosine phosphorylase (MTAP) was increased in human hearts with hypertrophic cardiomyopathy. The urine adenine/creatinine ratio in patients was predictive of incident heart failure with preserved ejection fraction. Heart adenine and MTAP gene expression was increased in a 2-hit mouse model of hypertrophic heart disease and in a model of diastolic dysfunction with diabetes. Inhibition of MTAP blocked adenine accumulation in the heart, restored heart dysfunction in mice with type 2 diabetes and prevented ischemic heart damage in a rat model of myocardial infarction. Mechanistically, adenine-induced impaired mitophagy was reversed by reduction of mTOR. These studies indicate that endogenous adenine is in a causal pathway for heart failure and ischemic heart disease in the context of CKM syndrome.
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