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(Hypertension. 2009;54:544.)
© 2009 American Heart Association, Inc.

Original Articles

Critical Role of Apoptosis Signal-Regulating Kinase 1 in Aldosterone/Salt-Induced Cardiac Inflammation and Fibrosis

Taishi Nakamura; Keiichiro Kataoka; Masaya Fukuda; Hisato Nako; Yoshiko Tokutomi; Yi-Fei Dong; Hidenori Ichijo; Hisao Ogawa; Shokei Kim-Mitsuyama

From the Departments of Pharmacology and Molecular Therapeutics (T.N., K.K., M.F., H.N., Y.T., Y.-F.D., S.K.-M.) and Cardiovascular Medicine (H.O.), Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan; Laboratory of Cell Signaling (H.I.), Tokyo University Graduate School of Pharmaceutical Sciences, Tokyo, Japan.

Correspondence to Shokei Kim-Mitsuyama, Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjyo, Kumamoto 860-8556, Japan. E-mail kimmitsu{at}gpo.kumamoto-u.ac.jp

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-β1 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.

Key Words: oxidative stress • inflammation • cross-talk • angiotensin • cardiac injury