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Identification of Noncoding Functional Regulatory Variants of STIM1 Gene in Idiopathic Pulmonary Arterial Hypertension.
- Source :
-
Hypertension (Dallas, Tex. : 1979) [Hypertension] 2024 Sep; Vol. 81 (9), pp. 1895-1909. Date of Electronic Publication: 2024 Jul 11. - Publication Year :
- 2024
-
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).<br />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 <superscript>2+</superscript> measurement were performed to study the mechanistic roles of those STIM1 noncoding variants in PAH.<br />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 <superscript>2+</superscript> 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.<br />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).<br />Competing Interests: None.
- Subjects :
- Humans
Male
Female
Case-Control Studies
Middle Aged
Adult
Neoplasm Proteins genetics
Myocytes, Smooth Muscle metabolism
Familial Primary Pulmonary Hypertension genetics
Familial Primary Pulmonary Hypertension physiopathology
Genetic Predisposition to Disease
Muscle, Smooth, Vascular metabolism
Gene Expression Regulation
Cell Proliferation genetics
Polymorphism, Single Nucleotide
Stromal Interaction Molecule 1 genetics
Stromal Interaction Molecule 1 metabolism
Pulmonary Artery
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4563
- Volume :
- 81
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Hypertension (Dallas, Tex. : 1979)
- Publication Type :
- Academic Journal
- Accession number :
- 38989583
- Full Text :
- https://doi.org/10.1161/HYPERTENSIONAHA.124.22766