title: CD38 mediates angiotensin II-induced intracellular Ca(2+) release in rat pulmonary arterial smooth muscle cells.
abstract: CD38 is a multifunctional enzyme that catalyzes the formation of the endogenous Ca(2+)-mobilizing messengers cyclic ADP-ribose (cADPR) and nicotinic acid adenosine dinucleotide phosphate (NAADP) for the activation of ryanodine receptors (RyRs) of sarcoplasmic reticulum and NAADP-sensitive Ca(2+) release channels in endolysosomes, respectively. It plays important roles in systemic vascular functions, but there is little information on CD38 in pulmonary arterial smooth muscle cells (PASMCs). Earlier studies suggested a redox-sensing role of CD38 in hypoxic pulmonary vasoconstriction. This study sought to characterize its roles in angiotensin II (Ang II)-induced Ca(2+) release (AICR) in PASMCs. Examination of CD38 expression in various rat arteries found high levels of CD38 mRNA and protein in pulmonary arteries. The Ang II-elicited Ca(2+) response consisted of extracellular Ca(2+) influx and intracellular Ca(2+) release in PASMCs. AICR activated in the absence of extracellular Ca(2+) was reduced by pharmacological or siRNA inhibition of CD38, by the cADPR antagonist 8-bromo-cADPR or ryanodine, and by the NAADP antagonist Ned-19 or disruption of endolysosomal Ca(2+) stores with the vacuolar H(+)-ATPase inhibitor bafilomycin A1. Suppression of AICR by the inhibitions of cADPR- and NAADP-dependent pathways were nonadditive, indicating interdependence of RyR- and NAADP-gated Ca(2+) release. Furthermore, AICR was inhibited by the protein kinase C inhibitor staurosporine, the nonspecific NADPH oxidase (NOX) inhibitors apocynin and diphenyleneiodonium, the NOX2-specific inhibitor gp91ds-tat, and the scavenger of reactive oxygen species (ROS) tempol. These results provide the first evidence that Ang II activates CD38-dependent Ca(2+) release via the NOX2-ROS pathway in PASMCs.
authors: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Suengwon
authors: S
authors: Lee
authors: Omkar
authors: O
authors: Paudel
authors: Yongliang
authors: Y
authors: Jiang
authors: Xiao-Ru
authors: XR
authors: Yang
authors: James S K
authors: JS
authors: Sham
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism*; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D009249:NADP / Q000031:analogs & derivatives / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D019837:Ryanodine Receptor Calcium Release Channel; D000804:Angiotensin II; D009249:NADP; C024376:NAADP; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D011493:Protein Kinase C; D051997:ADP-ribosyl Cyclase 1; D025262:Vacuolar Proton-Translocating ATPases; D002118:Calcium
keywords: CD38; NADPH oxidase; angiotensin II; cyclic ADP-ribose; nicotinic acid adenosine dinucleotide phosphate