Rieske Iron-Sulfur Protein-Dependent Mitochondrial ROS-Mediated Dissociation of FKBP12.6/RyR2 Complex Plays an Essential Role in Pulmonary Hypertension

Abstract

An abnormal increase in intracellular calcium concentration ([Ca2+]i, i.e., Ca2+ signaling) in pulmonary artery smooth muscle cells (PASMCs) has been generally believed to play an essential role in the development of pulmonary artery contraction and remodeling, thereby leading to devastating pulmonary hypertension. However, it is unclear which and how ion channels may mediate the abnormal increase in Ca2+ signaling in PASMCs and associated pulmonary hypertension. Herein we have for the first time found that RyR activity and Ca2+ release are significantly increased in PASMCs from mice with hypoxia-induced pulmonary hypertension, a most common type of pulmonary hypertension in clinic. Consistent with the increased RyR functions, SMC-specific RyR2 knockout (RyR2-/-) mice neither show the increased RyR activity and Ca2+ release nor develop pulmonary hypertension in mice following hypoxic exposure. Subcutaneous infusion of the RyR blocker tetracaine produces similar inhibitory effects. Our biochemical studies demonstrate that the endogenous RyR2 stabilizer (inhibitor) FK506 binding protein 12.6 (FKBP12.6) is dissociated from RyR2 in PASMCs from mice with pulmonary hypertension. FKBP12.6 knockout promotes, while subcutaneous infusion of the FKBP12.6 stabilizer S107 prevents, the development of pulmonary hypertension. Intravenous injection of lentiviral shRNAs specific for mitochondrial Rieske iron-sulfur protein (RISP) gene blocks the increased generation of PASMCs reactive oxygen species (ROS), dissociation of FKBP12.6/RyR2 complex, and pulmonary hypertension in mice. Taken together, we conclude that RISP-dependent mitochondrial ROS production may cause FKBP12.6/RyR2 complex dissociation, RyR2 hyperfunctions and Ca2+ release in PASMCs, which leads to pulmonary hypertension. Presumably, specific interventions targeted at RyR2, FKBP12.6 and RISP may become new and effective therapeutic strategies to treat pulmonary hypertension and other relevant vascular diseases.