title: Activation of JNK and xanthine oxidase by TNF-alpha impairs nitric oxide-mediated dilation of coronary arterioles.
abstract: Elevated levels of tumor necrosis factor-alpha (TNF), a proinflammatory cytokine, are associated with coronary artery disease. However, it is unclear whether vasodilator function of coronary resistance arterioles is susceptible to TNF. Herein, we examined whether TNF can affect endothelium-dependent nitric oxide (NO)-mediated dilation of coronary arterioles to adenosine and whether inflammatory signaling pathways such as mitogen-activated protein kinases, ceramide sphingolipids, and oxidative stress are involved in the TNF-mediated effect. To eliminate confounding influences associated with in vivo preparations, coronary arterioles from porcine heart were isolated and pressurized without flow for in vitro study. Intraluminal treatment with TNF (1 ng/ml, 90 min) significantly attenuated the NO release and vasodilation to adenosine. This inhibitory effect was not observed in denuded vessels or in the presence of NO synthase inhibitor l-NMMA. Histochemical data showed that superoxide production and JNK phosphorylation in arteriolar endothelial cells was enhanced by TNF. Administration of superoxide scavenger or inhibitors of ceramide-activated protein kinase (dimethylaminopurine), JNK (SP600125 and dicumarol), and xanthine oxidase (allopurinol) reduced superoxide production as well as restored NO release and vasodilation to adenosine. Conversely, the effects of TNF were insensitive to inhibitors of p38 (SB203580), ERK (PD98059), NAD(P)H oxidase (apocynin), or mitochondrial respiratory chain (rotenone). These data indicate that TNF inhibits endothelium-dependent NO-mediated dilation of coronary arterioles by ceramide-induced activation of JNK and subsequent production of superoxide via xanthine oxidase. Because myocardial ischemia augments adenosine production and elevates TNF level, inhibiting adenosine-stimulated endothelial release of NO by TNF could contribute to inadequate regulation of coronary blood flow during the development of ischemic heart disease.
authors.affiliation: Department of Medical Physiology, Cardiovascular Research Institute, College of Medicine, The Texas A&M University System Health Science Center, 702 Southwest H.K. Dodgen Loop, Temple, TX 76504, USA.
authors.forename: Cuihua
authors.initials: C
authors.lastname: Zhang
authors.forename: Travis W
authors.initials: TW
authors.lastname: Hein
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Yi
authors.initials: Y
authors.lastname: Ren
authors.forename: Robert D
authors.initials: RD
authors.lastname: Shipley
authors.forename: Lih
authors.initials: L
authors.lastname: Kuo
mesh_terms: D000241:Adenosine / Q000502:physiology; D000818:Animals; D001160:Arterioles / Q000201:enzymology*; D002518:Ceramides / Q000502:physiology; D003331:Coronary Vessels / Q000201:enzymology*; D004579:Electron Transport / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008928:Mitochondria / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D019255:NADPH Oxidases / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013108:Sphingomyelin Phosphodiesterase / Q000502:physiology; D013481:Superoxides / Q000378:metabolism; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D014652:Vascular Diseases / Q000201:enzymology; D014664:Vasodilation / Q000502:physiology; D014969:Xanthine Oxidase / Q000378:metabolism*
chemical_list: D002518:Ceramides; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D009569:Nitric Oxide; D014969:Xanthine Oxidase; D019255:NADPH Oxidases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D013108:Sphingomyelin Phosphodiesterase; D000241:Adenosine