Sotatercept Reverses SIN3a Deficiency-Driven PAH by Reprogramming BMPR2/TGF-β-HIF-1α Signaling Pathways
Year: 2026
Type: preprint
Abstract: Background: Pulmonary arterial hypertension is a progressive and fatal cardiopulmonary disease marked by excessive proliferation of pulmonary artery smooth muscle cells (PASMCs), pathological vascular remodeling, and ultimately right heart failure. Dysregulated BMPR2 signaling is a central molecular hallmark of PAH and is often associated with epigenetic suppression of BMPR2 expression. Switch-independent 3a (SIN3a), a transcriptional co-regulator and chromatin-modifying scaffold protein, has emerged as a key regulator of BMPR2 expression, yet its role in PAH pathogenesis remains poorly defined. Methods: ) in vitro. Comprehensive transcriptomic profiling and pathway analyses identified molecular networks regulated by SIN3a and Sotatercept. Hemodynamic measurements and detailed morphometric analyses were used to assess disease severity and treatment response. Results: SIN3a overexpression in PASMCs suppressed hypoxia-inducible factor-1α and TGF-β/SMAD2/3 signaling, restored BMPR2 expression, and activated canonical BMP signaling through SMAD1/5/9 phosphorylation, while reducing pro-inflammatory, oxidative, and fibrotic gene programs. Transcriptomic analyses revealed that SIN3a and Sotatercept converge on gene networks that regulate BMPR2 signaling, ID isoforms, extracellular matrix remodeling, oxidative stress, and inflammation. In vivo, smooth muscle-specific SIN3a deletion exacerbated Sugen/hypoxia-induced PAH, increasing right ventricular systolic pressure, right ventricular hypertrophy, pulmonary vascular remodeling, and fibrosis. Sotatercept treatment reversed these pathological features, restored SIN3a and BMPR2 expression, reactivated BMP signaling, and attenuated HIF-1α and TGF-β signaling in SIN3a-deficient mice. Conclusions: SIN3a is a central epigenetic regulator of PASMC homeostasis that integrates oxidative stress, inflammation, and fibrotic signaling. Loss of SIN3a accelerates PAH progression, whereas Sotatercept restores SIN3a expression, rebalances BMPR2 and TGF-β signaling, and attenuates pulmonary vascular remodeling and right ventricular dysfunction. Together, these findings identify SIN3a as a disease-relevant therapeutic target and support the use of Sotatercept as a disease-modifying approach for pulmonary vascular disease.
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Emerging Role of SIN3a/FOXK2 Complex in Pulmonary Endothelial cells, G2311987698, G2909542037, Targeting Endothelial SIN3A Using Lung-Specific mRNA Therapy In Pulmonary Arterial Hypertension, Role of SIN3a in the epigenetic regulation of the Bone Morphogenetic Protein Receptor Type 2 in pulmonary arterial hypertension, ARID1a and Chromatin Landscape in Pulmonary Vascular Disease, Role of Epigenetic Regulator SIN3a in Pulmonary Endothelial Cells, Role of Epac1 in the Pathogenesis of Pulmonary Fibrosis, Health AI and Data Science in Cardiovascular and Pulmonary Disease: Application and Bioethics (HARP-BIO), The Chromatin Remodeling Factor ARID1a and the Epigenetic Landscape In Pulmonary Arterial Hypertension
OpenAlex ID: W7127377538