PINK1/Parkin Deficiency Enhances Vascular Remodeling and Aggravates Hypoxia-induced Pulmonary Hypertension

Abstract

Alterations in mitochondrial structure and function contribute to vascular smooth muscle cell (VSMC) phenotypic switching and are causally linked to pulmonary arterial hypertension (PAH) pathogenesis. The PINK1/Parkin-mediated mitophagy pathway is a key mitochondrial quality control program by which defective mitochondria are targeted for removal. The role of PINK1/Parkin-mediated mitophagy in VSMC phenotypic switching and PAH pathogenesis is not known. We sought to evaluate if PINK1/Parkin-induced mitophagy modulates VSMC phenotypic switching and contributes to PAH. Mitophagy and PINK1/Parkin expression were evaluated in human PAH lungs and Pulmonary Artery Smooth Muscle Cells (PASMCs). PINK1 and Parkin were silenced in human and mouse primary PASMCs and global PINK1 and Parkin knockout mice were used. After silencing of PINK1 and Parkin, PASMC proliferation and apoptosis were measured, and experimental pulmonary hypertension was evaluated after exposure to hypoxia. Parkin and PINK1 levels were reduced in the pulmonary vasculature or PASMCs from PAH lungs, accompanied by decreased mitophagy. PINK1 and Parkin knockout animals had an exaggerated pulmonary hypertension phenotype upon exposure to hypoxia. Genetic silencing of PINK1 and Parkin in human and mouse PASMCs led to increased proliferation and apoptosis resistance. We conclude that Reduced PINK1/Parkin-induced mitophagy contributes to pulmonary artery smooth muscle cell phenotypic switching and exacerbates PAH.

Keywords: mitophagy, phenotypic switch, vascular smooth muscle, apoptosis resistance, pulmonary hypertension.