Alterations in Intracellular Ca2+ Release via CD38‐Dependent Pathways in Pulmonary Arterial Smooth Muscle of Rat by Chronic Hypoxia

Abstract

CD38 is a multifunctional enzyme for synthesis of cyclic ADP‐ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP), which activate ryanodine receptors of sarcoplasmic reticulum and NAADP‐sensitive two‐pore channels (TPCs) of lysosomal stores, respectively, leading to intracellular Ca2+ release. It is thought to play important roles in regulation of intracellular Ca2+ concentration ([Ca2+]i) and vascular functions. Ca2+ homeostasis in pulmonary arteries (PAs) is altered during the development of pulmonary hypertension by chronic hypoxia (CH). However, it still remains unclear whether those CD38–dependent pathways are affected. Here, we examined the changes in the expression of CD38 and TPCs in endothelium denuded PA, and angiotensin II (AngII)‐induced Ca2+ release (AICR) in PA smooth muscle cells (PASMCs). The expressions of CD38 and TPCs in PAs of CH rats were significantly increased. In addition, AICR was found to be mediated in part via the CD38‐dependent pathways. AICR in PASMCs with hypoxic exposure was significantly enhanced compared to control and was reduced by various types of inhibitors for the CD38‐dependent pathway. In summary, our results show that CH exposure leads to changes in expression of CD38 and TPC1/2 in PA smooth muscle as well as increased their associated responses in PASMCs, which may contribute to the alterations in Ca2+ homeostasis. (Supported by R01‐HL075134)