Identification of Noncoding Functional Regulatory Variants of <i>STIM1</i> Gene in Idiopathic Pulmonary Arterial Hypertension-Reference-Cited by-同舟云学术

Identification of Noncoding Functional Regulatory Variants of STIM1 Gene in Idiopathic Pulmonary Arterial Hypertension

Published:2024-09 Issue:9 Volume:81 Page:1895-1909
ISSN:0194-911X
Container-title:Hypertension
language:en
Short-container-title:Hypertension

Author:

Liu Bingxun¹²,Wen Cen-Jin³⁴^ORCID,Zhou Guangyuan¹²,Wei Yun-Peng³^ORCID,Wu Zeang¹²^ORCID,Zhang Ting¹²,Zhou Yudan¹²,Qiu Shuyi¹²,Wang Tao²⁵,Ruiz Matthieu⁶⁷,Dupuis Jocelyn⁸⁷^ORCID,Yuan Ping⁹,Liu Jinming⁹,Zhu Liping¹²,Jing Zhi-Cheng⁴^ORCID,Hu Qinghua¹²^ORCID

Affiliation:

1. Department of Pathophysiology, School of Basic Medicine (B.L., G.Z., Z.W., T.Z., Y.Z., S.Q., L.Z., Q.H.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

2. Key Laboratory of Pulmonary Diseases of Ministry of Health (B.L., G.Z., Z.W., T.Z., Y.Z., S.Q., T.W., L.Z., Q.H.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

3. Department of Cardiology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (C.-J.W., Y.-P.W.).

4. Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China (C.-J.W., Z.-C.J.).

5. Department of Respiratory and Critical Care Medicine, Tongji Hospital (T.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

6. Department of Nutrition (M.R.), Université de Montréal, Québec, Canada.

7. Montreal Heart Institute, Québec, Canada (M.R., J.D.).

8. Department of Medicine (J.D.), Université de Montréal, Québec, Canada.

9. Department of Cardiopulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, China (P.Y., J.L.).

Abstract

BACKGROUND: STIM1 (stromal interaction molecule 1) regulates store-operated calcium entry and is involved in pulmonary artery vasoconstriction and pulmonary artery smooth muscle cell proliferation, leading to pulmonary arterial hypertension (PAH). METHODS: Bioinformatics analysis and a 2-stage matched case-control study were conducted to screen for noncoding variants that may potentially affect STIM1 transcriptional regulation in 242 patients with idiopathic PAH and 414 healthy controls. Luciferase reporter assay, real-time quantitative polymerase chain reaction, western blot, 5-ethynyl-2’-deoxyuridine (EdU) assay, and intracellular Ca 2+ measurement were performed to study the mechanistic roles of those STIM1 noncoding variants in PAH. RESULTS: Five noncoding variants (rs3794050, rs7934581, rs3750996, rs1561876, and rs3750994) were identified and genotyped using Sanger sequencing. Rs3794050, rs7934581, and rs1561876 were associated with idiopathic PAH (recessive model, all P <0.05). Bioinformatics analysis showed that these 3 noncoding variants possibly affect the enhancer function of STIM1 or the microRNA (miRNA) binding to STIM1 . Functional validation performed in HEK293 and pulmonary artery smooth muscle cells demonstrated that the noncoding variant rs1561876-G ( STIM1 mutant) had significantly stronger transcriptional activity than the wild-type counterpart, rs1561876-A, by affecting the transcriptional regulatory function of both hsa-miRNA-3140-5p and hsa-miRNA-4766-5p. rs1561876-G enhanced intracellular Ca 2+ signaling in human pulmonary artery smooth muscle cells secondary to calcium-sensing receptor activation and promoted proliferation of pulmonary artery smooth muscle cells under both normoxia and hypoxia conditions, suggesting a possible contribution to PAH development. CONCLUSIONS: The potential clinical implications of the 3 noncoding variants of STIM1 , rs3794050, rs7934581, and rs1561876, are 2-fold, as they may help predict the risk and prognosis of idiopathic PAH and guide investigations on novel therapeutic pathway(s).

Publisher

Ovid Technologies (Wolters Kluwer Health)

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