title: NAD(P)H oxidase-dependent intracellular and extracellular O2•- production in coronary arterial myocytes from CD38 knockout mice.
abstract: Activation of NAD(P)H oxidase has been reported to produce superoxide (O(2)(•-)) extracellularly as an autocrine/paracrine regulator or intracellularly as a signaling messenger in a variety of mammalian cells. However, it remains unknown how the activity of NAD(P)H oxidase is regulated in arterial myocytes. Recently, CD38-associated ADP-ribosylcyclase has been reported to use an NAD(P)H oxidase product, NAD(+) or NADP(+), to produce cyclic ADP-ribose (cADPR) or nicotinic acid adenine dinucleotide phosphate, which mediates intracellular Ca(2+) signaling. This study was designed to test a hypothesis that the CD38/cADPR pathway as a downstream event exerts feedback regulatory action on the NAD(P)H oxidase activity in production of extra- or intracellular O(2)(•-) in mouse coronary arterial myocytes (CAMs). By fluorescence microscopic imaging, we simultaneously monitored extra- and intracellular O(2)(•-) production in wild-type (CD38(+/+)) and CD38 knockout (CD38(-/-)) CAMs in response to oxotremorine (OXO), a muscarinic type 1 receptor agonist. It was found that CD38 deficiency prevented OXO-induced intracellular but not extracellular O(2)(•-) production in CAMs. Consistently, the OXO-induced intracellular O(2)(•-) production was markedly inhibited by CD38 shRNA or the CD38 inhibitor nicotinamide in CD38(+/+) CAMs. Further, Nox4 siRNA inhibited OXO-induced intracellular but not extracellular O(2)(•-) production, whereas Nox1 siRNA attenuated both intracellular and extracellular O(2)(•-) production in CD38(+/+) CAMs. Direct delivery of exogenous cADPR into CAMs markedly elevated intracellular Ca(2+) and O(2)(•-) production in CD38(-/-) CAMs. Functionally, CD38 deficiency or Nox1 siRNA and Nox4 siRNA prevented OXO-induced contraction in isolated perfused coronary arteries in CD38 WT mice. These results provide direct evidence that the CD38/cADPR pathway is an important controller of Nox4-mediated intracellular O(2)(•-) production and that CD38-dependent intracellular O(2)(•-) production is augmented in an autocrine manner by CD38-independent Nox1-derived extracellular O(2)(•-) production in CAMs.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Xia
authors.forename: Xiao-Xue
authors.initials: XX
authors.lastname: Li
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Ritter
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Pin-Lan
authors.initials: PL
authors.lastname: Li
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D020013:Calcium Signaling; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology* / Q000187:drug effects; D036563:Cyclic ADP-Ribose / Q000494:pharmacology; D005260:Female; D055785:Gene Knockdown Techniques; D055786:Gene Knockout Techniques; D006861:Hydrogen Peroxide / Q000378:metabolism; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018721:Muscarinic Agonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D009536:Niacinamide / Q000494:pharmacology; D010095:Oxotremorine / Q000494:pharmacology; D043643:Receptor, Muscarinic M1 / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*
chemical_list: D007527:Isoenzymes; D008562:Membrane Glycoproteins; D018721:Muscarinic Agonists; D043643:Receptor, Muscarinic M1; D013481:Superoxides; D036563:Cyclic ADP-Ribose; D009536:Niacinamide; D010095:Oxotremorine; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1
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