Smooth muscle acid-sensing ion channel 1: pathophysiological implication in hypoxic pulmonary hypertension

Abstract

What is the topic of this review? An increase in pulmonary arterial smooth muscle cell intracellular Ca(2+) levels facilitates the enhanced vasoconstrictor and vascular remodeling responses associated with hypoxic pulmonary hypertension. Identifying the mechanisms of altered Ca(2+) homeostasis will advance our understanding of the pathogenesis of pulmonary hypertension and identify potential therapeutic targets. What advances does it highlight? Acid sensing ion channel 1 (ASIC1), present in pulmonary arterial smooth muscle cells, contributes to enhanced Ca(2+) entry and is an important constituent to the active vasoconstriction, vascular remodeling, and right ventricular hypertrophy associated with hypoxic pulmonary hypertension. Acid-sensing ion channels (ASICs) belong to the amiloride-sensitive, degenerin/epithelial sodium channel superfamily. Acid-sensing ion channels are voltage-independent, proton-gated cation channels, and their activity has been linked to a variety of physiological and pathological functions in the central and peripheral nervous system. Nonetheless, ASICs are expressed in a variety of tissues. In this review, we describe a novel role for ASIC1 in regulating pulmonary arterial smooth muscle cell (PASMC) Ca(2+) influx in both physiological and pathophysiological settings. Through a store-operated mechanism, ASIC1 contributes to pulmonary vasoconstriction elicited by various agonists and alveolar hypoxia. The ASIC1-mediated Ca(2+) entry in PASMCs is a central component of the active vasoconstriction, vascular remodelling and right ventricular hypertrophy associated with the development of hypoxic pulmonary hypertension. Despite the requirement for ASIC1 to enhance Ca(2+) influx in the pulmonary hypertensive circulation, these responses are not dependent on an increase in PASMC ASIC1 protein expression, suggesting that hypoxia promotes activation of ASIC1 through other regulatory mechanism(s). Here, I describe some of the correlations between hypoxia-induced changes in homeostasis of reactive oxygen species with that of ASIC1 function. Ultimately, a better understanding of the molecular mechanisms by which ASICs are regulated will help to elucidate their mechanism of action and identify potential therapeutics that specifically target ASICs.