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Mechanosensitive Stanniocalcin-1 Suppresses Smooth Muscle Cell Proliferation and Attenuates Experimental Pulmonary Hypertension

ABSTRACT: Background: Idiopathic pulmonary arterial hypertension (IPAH) is driven by progressive pulmonary vascular remodeling, particularly pulmonary arterial smooth muscle cell (PASMC) proliferation. Current combination vasodilator therapies have markedly improved outcomes; however, prognosis remains poor in subgroups such as patients with respiratory comorbidities, highlighting the need for novel therapies. Elevation of intravascular hydrostatic pressure is a hallmark of IPAH, yet its direct role in PASMC pathobiology remains largely unexplored. We developed a cyclic hydrostatic pressurization culture system to model hypertensive hemodynamic stress in vitro and identify pressure-responsive mediators. Methods: PASMCs from 4 patients with IPAH were exposed to high hydrostatic pressure (70/40 mmHg, 60 bpm). Transcriptomic profiling identified differentially expressed genes, validated by qPCR. Functional studies included piezo-type mechanosensitive ion channel component 1 (PIEZO1) modulation, recombinant human stanniocalcin-1 (rhSTC1) treatment, bromodeoxyuridine (BrdU) incorporation, and western blotting for cell-cycle regulators. In vivo, chronic hypoxia–induced pulmonary hypertension was assessed in wild-type and Stc1–/– mice by hemodynamic and histological analyses, with or without intratracheal rhSTC1 administration. Results: RNA sequencing revealed STC1 as a robustly pressure-induced gene in IPAH PASMCs. PIEZO1 activation upregulated STC1, whereas knockdown blunted this response. Elevated STC1 expression was observed in PASMCs of IPAH lung tissue and rhSTC1 reduced PASMC proliferation and increased p-p53, p21, and p27 expression. In the chronic hypoxia model, Stc1–/– mice exhibited higher right ventricular systolic pressure (RVSP) (43.7 ± 1.3 vs. 30.6 ± 0.9 mmHg) and greater pulmonary arterial medial thickness (39.1 ± 2.5% vs. 26.5 ± 1.3%) than wild-type mice. CD68-positive macrophages were increased in Stc1–/– mice under normoxia and further elevated with hypoxia. In wild-type and Stc1–/– PAH models, intratracheal administration of rhSTC1 markedly reduced medial thickening, and CD68-positive macrophage accumulation, and RVSP in both wild-type and Stc1–/– mice. Conclusions: We demonstrate, for the first time, that elevated hydrostatic pressure drives STC1 expression via PIEZO1, conferring potent anti-remodeling effects in IPAH. STC1 supplementation represents a promising therapeutic strategy that addresses an urgent medical need not fulfilled by conventional therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE317316 | GEO | 2026/09/05

REPOSITORIES: GEO

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Project description:Adenosine deaminase acting on RNA 1 (ADAR1) catalyzes the conversion of adenosine (A) to inosine (I) in double-stranded RNA (dsRNA), which is critical to prevent auto-inflammatory responses mediated by activation of the type I interferon (IFN) signaling. Here, we define the role of ADAR1-dependent RNA editing in interferon-β(IFNβ) activation and pulmonary artery smooth muscle cell (PASMC) remodeling in pulmonary arterial hypertension (PAH), a devastating disease leading to right heart failure and premature death. Methods: RNA editing levels were analyzed in human pulmonary artery smooth muscle cells (PASMCs) from idiopathic PAH (IPAH) patients versus healthy controls. A conditional transgenic line ADAR1SMC-KO was generated by knocking out ADAR1 selectively in α-smooth muscle actin-positive cells, followed by hypoxic exposure to induce PH. Results: PASMCs from IPAH patients displayed decreased levels of ADAR1 mRNA and protein, accompanied by reduced A-to-I editing compared to healthy PASMCs. ADAR1 knockdown in PASMCs upregulated MDA5, PKR, IFN-β and IFN-Stimulated Genes (ISGs). Compared with controls in vivo, hypoxic ADAR1SMC-KO mice developed severe PH, as evidenced by excessive vascular remodeling in distal arterioles and increased vascular leakage resulting in elevated right ventricular systolic pressure and right ventricular hypertrophy. Mechanistically, IFNβ signaling in ADAR1SMC-KO lungs induced the recruitment of inflammatory cells, including macrophages, which in turn enhanced PASMC proliferation and muscularization. Correspondingly, pharmacological treatment with PKR kinase inhibitor Imoxin decreased IFNβ thus attenuating the hypoxia-induced PH phenotype of ADAR1SMC-KO mice. Conclusions: ADAR1-dependent A-to-I RNA editing tempers IFN signaling in PASMCs. Pathologic reduction of ADAR1 in SMCs increased IFNβ activity, macrophage recruitment, and worsened PH, thus demonstrating a direct detrimental role of vascular innate immune responses in PH. Targeting PKR could be the new therapeutic strategy aimed at treating PAH.

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Mechanosensitive Stanniocalcin-1 Suppresses Smooth Muscle Cell Proliferation and Attenuates Experimental Pulmonary Hypertension

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