title: Critical role of apoptosis signal-regulating kinase 1 in aldosterone/salt-induced cardiac inflammation and fibrosis.
abstract: The molecular mechanism underlying aldosterone/salt-induced cardiovascular injury remains to be defined. This work was undertaken to determine the role of apoptosis signal-regulating kinase 1 (ASK1) in the mechanism underlying aldosterone-induced cardiac injury in vivo. We compared the in vivo effects of 4 weeks of aldosterone/salt treatment on wild-type and ASK1-deficient mice. Aldosterone infusion plus high salt intake in wild-type mice significantly increased blood pressure and urinary albumin excretion and decreased plasma potassium concentrations, and these effects of aldosterone/salt were not affected by ASK1 deficiency. Thus, ASK1 seems to play a minor role in aldosterone-induced hypertension and renal injury. ASK1 deficiency also failed to affect aldosterone-induced cardiac hypertrophy. However, ASK1 deficiency markedly ameliorated aldosterone-induced cardiac injury, eg, the enhancement of cardiac macrophage infiltration, monocyte chemotactic protein 1 expression, interstitial fibrosis, perivascular fibrosis, and transforming growth factor-beta1 and collagen type I expressions. Thus, ASK1 participates in aldosterone-induced cardiac inflammation and fibrosis. Furthermore, the enhancement of NADPH oxidase-mediated cardiac oxidative stress caused by aldosterone infusion was markedly lessened by ASK1 deficiency, which was associated with the significant amelioration by ASK1 deficiency of aldosterone-induced cardiac Nox2 upregulation. Furthermore, aldosterone/salt treatment significantly enhanced cardiac expression of the angiotensin-converting enzyme and angiotensin II type 1 receptor in wild-type mice, whereas the enhancement of these proteins by aldosterone/salt was abolished by ASK1 deficiency. Our results demonstrate that ASK1 is implicated in aldosterone/salt-induced cardiac inflammation and fibrosis through the enhancement of NADPH oxidase-mediated oxidative stress and the upregulation of the cardiac renin-angiotensin system.
authors: Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjyo, Kumamoto 860-8556, Japan. kimmitsu@gpo.kumamoto-u.ac.jp.
authors: Taishi
authors: T
authors: Nakamura
authors: Keiichiro
authors: K
authors: Kataoka
authors: Masaya
authors: M
authors: Fukuda
authors: Hisato
authors: H
authors: Nako
authors: Yoshiko
authors: Y
authors: Tokutomi
authors: Yi-Fei
authors: YF
authors: Dong
authors: Hidenori
authors: H
authors: Ichijo
authors: Hisao
authors: H
authors: Ogawa
authors: Shokei
authors: S
authors: Kim-Mitsuyama
mesh_terms: D000419:Albuminuria / Q000652:urine; D000450:Aldosterone / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D018932:Chemokine CCL2 / Q000235:genetics; D005260:Female; D005355:Fibrosis / Q000097:blood / Q000209:etiology / Q000652:urine; D015870:Gene Expression / Q000187:drug effects; D007249:Inflammation / Q000097:blood / Q000209:etiology / Q000652:urine; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D019255:NADPH Oxidases / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D011188:Potassium / Q000097:blood; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D012964:Sodium / Q000097:blood; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage / Q000633:toxicity*; D013481:Superoxides / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D044140:Receptor, Angiotensin, Type 1; D017673:Sodium Chloride, Dietary; D053773:Transforming Growth Factor beta1; D013481:Superoxides; D000450:Aldosterone; D012964:Sodium; D019255:NADPH Oxidases; D020928:Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; D007703:Peptidyl-Dipeptidase A; D011188:Potassium