Cross Talk Between Mitochondrial Reactive Oxygen Species and Sarcoplasmic Reticulum Calcium in Pulmonary Arterial Smooth Muscle Cells

Abstract

Hypoxic pulmonary vasoconstriction (HPV) occurs during both fetal and postnatal development and plays a critical role in matching regional alveolar perfusion with ventilation in humans and animals. HPV also contributes significantly to the development of pulmonary hypertension. Although the molecular mechanisms of HPV and pulmonary hypertension remain incompletely understood, increasing evidence demonstrates that hypoxia induces an elevated intracellular reactive oxygen species concentration ([ROS]_i) in pulmonary artery smooth muscle cells (PASMCs). The increased [ROS]_i is attributed to the mitochondrial electron transport chain (ETC) and plasmalemmal NADPH oxidase (NOX); however, the mitochondrial ETC is a primary source for the elevated [ROS]_i. Our studies reveal that mitochondrial ROS can specifically increase the activity of protein kinase C-ε, activate NOX, and then induce more ROS production (i.e., ROS-induced ROS production, RIRP). Mitochondrial ROS production is principally mediated by Rieske iron-sulfur protein (RISP) at the complex III. The increased [ROS]_i causes an elevation of intracellular Ca²⁺ concentration ([Ca²⁺]_i), thereby leading to HPV and associated pulmonary hypertension. Ryanodine receptor-2 (RyR2)/Ca²⁺ release channel on the sarcoplasmic reticulum (SR) serves as a most valuable player in the elevated [Ca²⁺]_i. Our recent data indicate that RyR2-induced Ca²⁺ release can enhance RISP-mediated increase in mitochondrial ROS concentration ([ROS]_mito), and that the mitochondrial Ca²⁺ uniporter is involved in elevating [ROS]_mito. Based on the existing reports and our unpublished data, we conclude that the cross talk between [ROS]_mito and [Ca²⁺]_i, that is RISP-dependent mitochondrial ROS-induced RyR2-mediated SR Ca²⁺ release (ROS-induced Ca²⁺ release, RICR) and RyR2-mediated SR Ca²⁺ release-induced RISP-dependent mitochondrial ROS production (Ca²⁺-induced ROS production, CIRP), may form a positive reciprocal loop in mediating HPV and also possibly pulmonary hypertension.

Keywords: Calcium-induced ROS production; Hypoxia; Inositol 1,4,5-trisphosphate receptor; Mitochondria; NADPH oxidase; Pulmonary hypertension; ROS-induced ROS production; ROS-induced calcium release; Rieske iron-sulfur protein; Ryanodine receptor.