B18-06 Sin3a Balances Bmp And Tgf-β Signaling To Mitigate Hypoxia-induced Pulmonary Hypertension Via Vascular Cell Crosstalk

Background Pulmonary arterial hypertension (PAH) is a progressive, deadly cardiopulmonary disease caused by excessive proliferation of PASMCs, leading to vascular remodeling and right heart failure. A hallmark of PAH is the suppression of BMPR2 signaling, frequently attributed to epigenetic regulation. Switch-independent 3A (SIN3a), a transcriptional co-regulator and chromatin-modifying scaffold protein, has been identified as a key regulator of BMPR2 expression. However, its precise role in modulating PASMC phenotype and function in PAH pathogenesis remains poorly understood. Methods Conditional SMC-deficient specific Sin3a KO mice were generated and subjected to Sugen and chronic hypoxia (SuHx) environmental stress for three weeks to induce a PAH phenotype, then treated with Sotatercept for two weeks. The hemodynamic and morphometric assessments were carried out to evaluate the impact of SIN3a deletion and sotatercept treatment on disease onset and progression. In parallel, an adenoviral vector encoding SIN3a was used in human PASMCs treated with either TGFβ1 or exposed to hypoxia (1% O2) to mimic the disease-associated microenvironment in vitro. Transcriptomic profiling analyses were also performed in PASMCs derived from PAH patients, to identify the molecular pathways regulated by SIN3a or Sotatercept treatments. Results SIN3a overexpression in PASMCs suppresses both hypoxia-inducible factor 1-alpha (HIF1α) and transforming growth factor-beta (TGF-β) signaling pathways, while restoring BMPR2 expression and phosphorylation of SMAD1/5/9, thereby activating canonical BMP signaling. Transcriptomic profiling in SIN3a or Sotatercept treated-PASMC derived from PAH patients regulates gene networks involved in oxidative stress, extracellular matrix (ECM) remodeling, and inflammation. ChIP-seq analysis confirmed that SIN3a targets chromatin regions associated with hypoxic and fibrotic responses, supporting SIN3a’s role as a chromatin-level regulator of PAH pathways. In in vivo studies, SMC-specific deletion of SIN3a exacerbated SuHx-induced PAH, evidenced by increased right ventricular systolic pressure (RVSP), RV hypertrophy, collagen deposition, and medial wall thickening, all of which were attenuated by Sotatercept. Consistent with the molecular phenotype observed in vitro, the Sotatercpt treatment in vivo reversed SIN3a deficiency-induced the expression of IL6, TNF-alpha, NADPH oxidase 4 (NOX4), and SMAD2/3, while BMPR2 and key antioxidant genes were downregulated. Conclusions SIN3a functions as a central epigenetic regulator of PASMC homeostasis, integrating responses to oxidative stress, inflammation, and fibrotic signaling. SIN3a loss disrupts these regulatory networks, leading to dysregulated signaling cascades and accelerated PAH progression. These findings position Sotatercept as a promising therapeutic target in the treatment of pulmonary vascular diseases with reduced SIN3a levels. This abstract is funded by: 5R01HL172043