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Identification of Noncoding Functional Regulatory Variants of STIM1 Gene in Idiopathic Pulmonary Arterial Hypertension.
Liu, Bingxun; Wen, Cen-Jin; Zhou, Guangyuan; Wei, Yun-Peng; Wu, Zeang; Zhang, Ting; Zhou, Yudan; Qiu, Shuyi; Wang, Tao; Ruiz, Matthieu; Dupuis, Jocelyn; Yuan, Ping; Liu, Jinming; Zhu, Liping; Jing, Zhi-Cheng; Hu, Qinghua.
Afiliación
  • Liu B; Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (B.L., G.Z., Z.W., T.Z., Y.Z., S.Q., L.Z., Q.H.).
  • Wen CJ; Key Laboratory of Pulmonary Diseases of Ministry of Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (B.L., G.Z., Z.W., T.Z., Y.Z., S.Q., T.W., L.Z., Q.H.).
  • Zhou G; 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.).
  • Wei YP; 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.).
  • Wu Z; Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (B.L., G.Z., Z.W., T.Z., Y.Z., S.Q., L.Z., Q.H.).
  • Zhang T; Key Laboratory of Pulmonary Diseases of Ministry of Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (B.L., G.Z., Z.W., T.Z., Y.Z., S.Q., T.W., L.Z., Q.H.).
  • Zhou Y; 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.).
  • Qiu S; Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (B.L., G.Z., Z.W., T.Z., Y.Z., S.Q., L.Z., Q.H.).
  • Wang T; Key Laboratory of Pulmonary Diseases of Ministry of Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (B.L., G.Z., Z.W., T.Z., Y.Z., S.Q., T.W., L.Z., Q.H.).
  • Ruiz M; Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (B.L., G.Z., Z.W., T.Z., Y.Z., S.Q., L.Z., Q.H.).
  • Dupuis J; Key Laboratory of Pulmonary Diseases of Ministry of Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (B.L., G.Z., Z.W., T.Z., Y.Z., S.Q., T.W., L.Z., Q.H.).
  • Yuan P; Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (B.L., G.Z., Z.W., T.Z., Y.Z., S.Q., L.Z., Q.H.).
  • Liu J; Key Laboratory of Pulmonary Diseases of Ministry of Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (B.L., G.Z., Z.W., T.Z., Y.Z., S.Q., T.W., L.Z., Q.H.).
  • Zhu L; Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (B.L., G.Z., Z.W., T.Z., Y.Z., S.Q., L.Z., Q.H.).
  • Jing ZC; Key Laboratory of Pulmonary Diseases of Ministry of Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (B.L., G.Z., Z.W., T.Z., Y.Z., S.Q., T.W., L.Z., Q.H.).
  • Hu Q; Key Laboratory of Pulmonary Diseases of Ministry of Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (B.L., G.Z., Z.W., T.Z., Y.Z., S.Q., T.W., L.Z., Q.H.).
Hypertension ; 2024 Jul 11.
Article en En | MEDLINE | ID: mdl-38989583
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 Ca2+ 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 Ca2+ 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).
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Hypertension Año: 2024 Tipo del documento: Article
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Hypertension Año: 2024 Tipo del documento: Article