Sodium tanshinone IIA sulfonate attenuates pulmonary vascular remodeling by targeting DYRK1A in pulmonary hypertension.
Abstract
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 (DYRK1AKI 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. DYRK1AKI 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 metabolism from oxidative phosphorylation to glycolysis, thereby accelerating PA remodeling. Targeting DYRK1A with STS restores mitochondrial function, attenuates PASMC phenotypic transition and alleviates vascular remodeling.