Vitamin D Attenuates Inflammation and Mitochondrial Dysfunction in Experimental Models Relevant to Connective Tissue Disease-Associated Pulmonary Arterial Hypertension.

Vitamin D (VD) deficiency is prevalent in chronic inflammatory disorders and has been implicated in cardiopulmonary diseases. This study investigated whether VD, as a nutritional factor, modulates inflammatory and mitochondrial homeostasis in experimental pulmonary arterial hypertension (PAH) models and explored mechanisms with potential relevance to connective tissue disease-associated PAH (CTD-PAH). A monocrotaline-induced rat model and PDGF-BB/hypoxia-treated pulmonary artery smooth muscle cells (PASMCs) were used. Hemodynamics, right ventricular remodeling, and vascular structure were assessed by catheterization and histology. Inflammatory cytokines, mitochondrial function, and apoptosis were evaluated by Enzyme-Linked Immunosorbent Assay (ELISA), JC-1, ROS, ATP assays, and related protein analyses. Western blot, quantitative real-time polymerase chain reaction (qRT-PCR), PARP1 activity, and co-immunoprecipitation were performed to examine NF-κB regulation via the Hes1-PARP1 axis and TNFAIP3. VD supplementation improved pulmonary hemodynamics, reduced right ventricular hypertrophy, and attenuated pulmonary vascular remodeling. In PASMCs, VD suppressed abnormal proliferation, promoted apoptosis, and restored mitochondrial homeostasis. Mechanistically, VD downregulated the Hes1-PARP1 axis while upregulating TNFAIP3, leading to inhibition of NF-κB activation and inflammatory signaling. VD modulates inflammatory and mitochondrial homeostasis in experimental PAH models through coordinated regulation of the Hes1-PARP1 axis and TNFAIP3. These findings support VD as a nutritional factor involved in modulating inflammatory and mitochondrial homeostasis during early PAH progression, and provide mechanistic support for VD-related nutritional strategies with relevance to CTD-PAH-associated pulmonary vascular remodeling.