title: Apoptosis signal-regulating kinase-1 is involved in vascular endothelial and cardiac remodeling caused by nitric oxide deficiency.
abstract: Long-term treatment with N(omega)-nitro-l-arginine methylester (l-NAME), an NO synthase inhibitor, induces hypertension and cardiovascular injury. However, its precise mechanism is unknown. Using apoptosis signal-regulating kinase-1 (ASK1)-deficient mice, we investigated the role of ASK1 in cardiovascular injury caused by l-NAME treatment. l-NAME was orally administered to ASK1-deficient and C57BL/6J (wild) mice for 8 weeks. l-NAME treatment increased blood pressure of wild and ASK1-deficient mice to a similar extent, indicating no role of ASK1 in NO-deficient hypertension. l-NAME treatment significantly impaired acetylcholine-induced carotid arterial relaxation in wild mice (P<0.01), being associated with the decreased endothelial NO synthase (eNOS) activity (P<0.01) and the increased disruption of eNOS dimer (P<0.01), whereas these changes by l-NAME were substantially attenuated in ASK1-deficient mice. Thus, ASK1 is involved in the impairment of vascular endothelial function by reducing eNOS activity and disrupting eNOS dimer. l-NAME treatment increased vascular reduced nicotinamide-adenine dinucleotide phosphate oxidase activity and superoxide in wild mice to a greater extent than in ASK1 deficient mice. l-NAME treatment in wild mice caused cardiac hypertrophy, myocyte apoptosis, macrophage infiltration, coronary arterial remodeling, interstitial fibrosis, and the expression of monocyte chemoattractant protein-1 and transforming growth factor-beta1, whereas these cardiac changes by l-NAME were absent in ASK1-deficient mice. Cardiac reduced nicotinamide-adenine dinucleotide phosphate oxidase activation and superoxide elevation by l-NAME were much less in ASK1-deficient mice than in wild mice. Our work provided the first evidence that ASK1 is implicated in vascular endothelial dysfunction and cardiovascular remodeling induced by NO deficiency by regulating eNOS and reduced nicotinamide-adenine dinucleotide phosphate oxidase.
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Yamashita
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Yamamoto
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Kataoka
authors.forename: Taishi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Shinji
authors.initials: S
authors.lastname: Matsuba
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Tokutomi
authors.forename: Yi-Fei
authors.initials: YF
authors.lastname: Dong
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
authors.forename: Hisao
authors.initials: H
authors.lastname: Ogawa
authors.forename: Shokei
authors.initials: S
authors.lastname: Kim-Mitsuyama
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000139:chemically induced / Q000473:pathology; D018932:Chemokine CCL2 / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048848:MAP Kinase Kinase Kinase 5 / Q000172:deficiency / Q000378:metabolism*; D008264:Macrophages / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D032342:Muscle Cells; D019255:NADPH Oxidases / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000172:deficiency*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D009589:Nitrogen Oxides / Q000097:blood; D013481:Superoxides / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D009589:Nitrogen Oxides; D016212:Transforming Growth Factor beta; D013481:Superoxides; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; D048848:MAP Kinase Kinase Kinase 5; D019331:NG-Nitroarginine Methyl Ester