丹参酮IIA磺酸钠通过靶向DYRK1A抑制肺动脉高压患者肺血管重构

Abstract

DYRK1A drives the phenotypic transition of PASMCs to fibroblast-like phenotype. • DYRK1A knockin accelerates the progression of pulmonary artery remodeling. • DYRK1A regulates mitochondrial energy metabolism via PKACA. • STS acts as a specific inhibitor of DYRK1A. Background Pulmonary hypertension (PH) is a progressive disorder marked by elevated pulmonary artery (PA) pressure and vascular remodeling, often leading to right heart failure. A key feature is pulmonary artery smooth muscle cells (PASMC) phenotypic switching from a contractile to a synthetic state, which drives medial hypertrophy and vascular occlusion. However, the role of DYRK1A in this process remains unclear. Objectives To elucidate DYRK1A's role in PH pathogenesis and identify novel pathways and potential therapeutic targets. Methods HySu-induced PH mice underwent PA profiling and smooth muscle cell (SMC)-specific DYRK1A knock-in (DYRK1A KI MYH11 ). Hemodynamics and remodeling were assessed. Transcriptomics and co-IP/MS mapped DYRK1A downstream effectors. Sodium tanshinone IIA sulfonate (STS) binding was characterized by pull-down, docking, and functional assays, and STS efficacy with DYRK1A targeting was evaluated in HySu-PH mice. Results DYRK1A was upregulated in PASMCs from PH models. DYRK1A KI MYH11 exacerbated PA remodeling in HySu-induced PH mice. Mechanistically, DYRK1A enhanced cyclic AMP-dependent protein kinase catalytic subunit alpha (PKACA) activity, which suppressed mitochondrial oxidative phosphorylation and augmented glycolysis, thereby driving PASMC phenotypic transition. Furthermore, STS directly bound and inhibited DYRK1A. This inhibition reduced PKACA activity, restored mitochondrial oxidative phosphorylation, attenuated glycolysis, and suppressed PASMC phenotypic transition. Through DYRK1A, STS alleviated pulmonary arterial remodeling in HySu-induced PH mice. Conclusions: DYRK1A promotes the phenotypic transition of PASMCs by increasing PKA activity, which shifts cellular me