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Am J Respir Cell Mol Biol
Am J Respir Cell Mol Biol
ajrcmb
American Journal of Respiratory Cell and Molecular Biology
1044-1549
1535-4989
American Thoracic Society

38749029
2024-0214ED
10.1165/rcmb.2024-0214ED
Editorials
Therapeutic Potential of Sodium Houttuyfonate in Pulmonary Hypertension through Orai-Ca2+ Channels
https://orcid.org/0000-0002-2078-3271
Saint-Martin Willer Anaïs 1 2
El Jekmek Kristell 1 2
https://orcid.org/0000-0002-9515-6571
Antigny Fabrice 1 2
1 Faculté de Médecine
Université Paris-Saclay
Le Kremlin-Bicêtre, France
2 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique
Hôpital Marie Lannelongue
Le Plessis-Robinson, France
15 5 2024
1 9 2024
15 5 2024
71 3 262263
Copyright © 2024 by the American Thoracic Society
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0. For commercial usage and reprints, please e-mail Diane Gern.

Fondation Maladies Rares and AFM-Téléthon POCs(2023)-121503
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pmcPulmonary arterial hypertension (PAH) is a rare, severe, and fatal disease caused by the progressive obstruction of small pulmonary arteries, which results in the elevation of mean pulmonary arterial pressure (>20 mm Hg), pulmonary vascular resistance (>2 Wood units), and pulmonary arterial wedge pressure ⩽15 mm Hg, leading to right ventricular (RV) failure and, ultimately, death (1). The prevalence of PAH is 48–55 cases per million, with 3-year mortality estimated at 30–55% with approved therapies, highlighting that current therapeutics are insufficient. Despite therapeutic improvements, lung transplantation remains the ultimate treatment for eligible patients (1). The pulmonary arterial obstruction occurring in PAH is multifactorial, involving pulmonary arterial smooth muscle cells (PASMCs) and pulmonary arterial endothelial cells. PASMCs from patients with PAH become more proliferative and resistant to apoptosis (2).

Dysregulation of intracellular calcium (Ca2+) signaling, especially store-operated Ca2+ entry (SOCE), is crucial in PASMC dysfunction and PAH pathogenesis (3). Store-operated Ca2+ channels have three essential components: stromal interaction molecule proteins that are endoplasmic and/or sarcoplasmic reticulum Ca2+  sensors, plasma membrane Orai Ca2+ channels, and transient receptor potential canonical (TRPC) channels. The Orai channel family includes three members: Orai1, Orai2, and Orai3. SOCE is increased in PASMCs from patients with PAH (3, 4) and from experimental PAH animals (5, 6). However, the molecular identity and mechanisms responsible for increased SOCE are not entirely understood.

In this issue of the Journal, Zhang and colleagues (pp. 332–342) investigated the contribution of Orai proteins in experimental PAH induced by monocrotaline (MCT) exposure in rats. In addition, they investigated the therapeutic potential of sodium houttuyfonate (SH) (7). SH, a product from the addition of sodium bisulfite and houttuynia, is an active natural compound isolated from the Houttuynia cordata plant that is mainly used in traditional Chinese medicine for its antiinflammatory and antimicrobial properties in treating purulent skin infections and respiratory tract infections, including pneumonia in elderly patients and chronic bronchitis (8). There is some evidence that SH reduces lung remodeling that is induced by triggers such as pneumonia, lung injury (8), and pulmonary fibrosis (9). In their paper, Zhang and colleagues show that Orai1 and Orai2 are upregulated in the lung, pulmonary arteries, and PASMCs from MCT-PAH rats without change in Orai3 expression.

Zhang and colleagues evaluated the consequence of the administration of SH on the severity and the development of PAH induced by MCT. Using preventive and curative protocols, they report that SH (100 mg/kg/d) strongly reduces indices of PAH, including RV systolic pressure, pulmonary vascular remodeling, in situ PASMC proliferation, RV hypertrophy, and fibrosis. In addition, in vivo administration of SH normalizes Orai1 and Orai2 expression in pulmonary arteries from MCT-PAH rats. They also provided evidence that SH treatment decreases SOCE, [Ca2+]i, and proliferation by means of Orai1 and Orai2 in PASMCs isolated from MCT-PAH rats (7). These findings suggest that a mechanism of action for SH is, in part, through the inhibition of Orai1 and Orai2 signaling.

Using a siRNA strategy to knockdown individual Orai isoforms, the authors demonstrated that the knockdown of either Orai1 or Orai2 alone, or Orai1 and Orai2 combined, reduced excessive SOCE, [Ca2+]i, and the proliferation of PASMCs isolated from MCT-PAH rats (7). These results show that Orai1 and Orai2 are key contributors to experimental PAH triggered by MCT exposure. This work confirms the importance of the Orai Ca2+ channels in the pathogenesis of PAH, previously highlighted by Masson and colleagues, and should be considered as an innovative therapeutic target (4). Moreover, Zhang and colleagues found that Orai1 and Orai2 overexpression attenuates the effect of SH on SOCE and the proliferation of PASMCs from MCT-PAH rats, reaffirming the involvement of SH effects on these channels, although the downstream pathways associated with Orai1 inhibition remain unclear. This report is unique in that the role of Orai2 was not previously established in PAH pathogenesis, although it can contribute to the transition of PASMCs from a contractile to a proliferative phenotype (10). As described earlier, SH appears to have beneficial effects on different lung injuries, and, considering the findings in this study, SH presents a promising therapeutic potential in PAH. The variety of SH effects is interesting with respect to pulmonary vascular remodeling, inflammation, and cardiac dysfunction. With the development of drug design, SH could be easily modified to improve its characteristics regarding its diverse properties (8).

Despite these areas of promise, some essential questions remain. The mechanism of action for SH remains unclear and needs further investigation. Notably, from Orai1- or Orai2-overexpression experiments, the authors suggest that the effects of SH on SOCE are not only entirely due to impact on Orai1 and Orai2. In the past decade, several publications have demonstrated the involvement of TRPC channels in the dysfunction of PASMCs from patients with PAH (increased SOCE, proliferation, apoptosis resistance, vasconstriction), and the development of experimental PAH (3, 11, 12). It would be interesting to determine the consequences of SH treatment on TRPC function. In line with this point, to clearly determine whether SH acts primarily as an Orai Ca2+ channel blocker, additional patch-clamp experiments are required to identify the effects of SH on Ca2+ channels more broadly. Because SH attenuates MCT-induced increases in SOCE and rat PASMC proliferation, it would be interesting to confirm the effect of SH on SOCE, proliferation, migration, and apoptosis in PASMCs from human donors with PAH. Furthermore, to move drug development potential forward, studies that determine the consequence of SH treatment on human pulmonary endothelial cell dysfunction are needed, as these cells are a main trigger of PAH pathogenesis. Undoubtedly, in the field of PAH and experimental PAH, the MCT-PAH model is recognized for its ability to recapitulate several crucial human PAH features. However, inflammation is a crucial mediator of PAH in this model. As SH appears to have antiinflammatory properties, these results need to be confirmed in another model of severe PAH, perhaps with a less significant inflammatory phenotype than the MCT-PAH model. In addition, there is an important need for further studies investigating the benefit of SH treatment in female animals, because PAH occurs predominantly among females (13).

In conclusion, Zhang and colleagues reinforce the concept that exacerbated SOCE contributes to PAH pathogenesis and that Orai Ca2+ channels constitute innovative targets to counteract PASMC dysfunction and pulmonary arterial remodeling. This work also suggests that SH possesses important properties that alleviate PAH. Further investigation is needed to fully decipher how SH exerts its protective effects and to determine how SH acts on Orai Ca2+ channel functions or Orai1 modulators (14), as well as its potential role in pulmonary endothelial cell dysfunction.

Acknowledgment

The authors thank Dr. Veronique Capuano for her help in writing this editorial.

Supported by grants from the French National Institute for Health and Medical Research (INSERM), the Université Paris-Saclay, the Marie Lannelongue Hospital, and the French National Agency for Research. This work was also supported by grant POCs(2023)-121503 from Fondation Maladies Rares and AFM-Téléthon and by a grant from the Therapeutic Innovation Doctoral School (ED569 to A.S.-M.W.).

Originally Published in Press as DOI: 10.1165/rcmb.2024-0214ED on May 15, 2024

Author disclosures are available with the text of this article at www.atsjournals.org.
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