Neuronal nitric oxide synthase negatively regulates xanthine oxidoreductase inhibition of cardiac excitation-contraction coupling.
Although interactions between superoxide (O(2)(.-)) and nitric oxide underlie many physiologic and pathophysiologic processes, regulation of this crosstalk at the enzymatic level is poorly understood. Here, we demonstrate that xanthine oxidoreductase (XOR), a prototypic superoxide O(2)(.-) -producing enzyme, and neuronal nitric oxide synthase (NOS1) coimmunoprecipitate and colocalize in the sarcoplasmic reticulum of cardiac myocytes. Deficiency of NOS1 (but not endothelial NOS, NOS3) leads to profound increases in XOR-mediated O(2)(.-) production, which in turn depresses myocardial excitation-contraction coupling in a manner reversible by XOR inhibition with allopurinol. These data demonstrate a unique interaction between a nitric oxide and an O(2)(.-) -generating enzyme that accounts for crosstalk between these signaling pathways; these findings demonstrate a direct antioxidant mechanism for NOS1 and have pathophysiologic implications for the growing number of disease states in which increased XOR activity plays a role.
Departments of Medicine (Cardiology Division) and Anesthesia and Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
Shakil A
SA
Khan
Kwangho
K
Lee
Khalid M
KM
Minhas
Daniel R
DR
Gonzalez
Shubha V Y
SV
Raju
Ankit D
AD
Tejani
Dechun
D
Li
Dan E
DE
Berkowitz
Joshua M
JM
Hare
D000818:Animals; D001483:Base Sequence; D020013:Calcium Signaling; D018076:DNA, Complementary / Q000235:genetics; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D018384:Oxidative Stress; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013347:Subcellular Fractions / Q000201:enzymology; D013481:Superoxides / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism*
D018076:DNA, Complementary; D013481:Superoxides; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496321:Nos1 protein, mouse; C496315:Nos3 protein, mouse; D014969:Xanthine Oxidase