CD38‐Dependent Ca2+ Signaling Mechanisms in Pulmonary Arterial Smooth Muscle is Altered in Hypoxic Pulmonary Hypertension

Abstract

Prolonged exposure to hypoxia causes chronic hypoxic pulmonary hypertension (CHPH), but the underlying mechanism is not fully understood. Accumulating evidence suggests aberrant Ca2+ homeostasis in pulmonary arterial smooth muscle cells (PASMCs). This study sought to characterize the effect of CH on the expression and functions of CD38, a multi‐functional enzyme that produces the Ca2+ mobilizing messengers cyclic ADP‐ribose and nicotinic acid adenine dinucleotide phosphate, in PASMCs. CD38 protein and mRNA were upregulated in pulmonary arteries (PAs) of CH rats. It was accompanied by significant increase in NADase activity, cADPR and NAADP levels. Angiotensin II‐induced Ca2+ release (AICR), which is mediated in part by CD38, was significantly increased in PASMCs of CH rats, and the increase was completely abolished by the CD38 inhibitor nicotinamide. Endothelium‐denuded PA of 1 week CH rat exhibited spontaneous rhythmic contraction, which was not observed in PA of normoxic rat. The spontaneous contractions were blocked by inhibitors of the CD38‐dependent pathways. CH‐induced CD38 upregulation was due to direct effect of hypoxia on PASMCs. Exposure of cultured PASMCs to hypoxia for 3 days caused significant increase in CD38 expression and enhancement in AICR, which was also suppressed by nicotinamide. CD38 upregulation in hypoxia exposed PASMCs was inhibited by the specific NFAT‐inhibitor VIVIT and cyclosporine A, indicating that it is mediated by the calcineurin/NFAT‐pathway. Our results indicate that CH has a profound effect on CD38‐dependent Ca2+ signaling in PASMCs, and these changes may play an important role in the development of CHPH. (supported by HL075134 and AHA GIA)