Published Online
on September 18, 2006

A more recent version of this article appeared on November 1, 2006

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Submitted on May 18, 2006
Revised on June 7, 2006

An Elastolytic Cathepsin Induction/Activation System Exists in Myocardium and Is Upregulated in Hypertensive Heart Failure

Xian Wu Cheng^*; Koji Obata; Masafumi Kuzuya; Hideo Izawa; Kae Nakamura; Eri Asai; Tetsuro Nagasaka; Masako Saka; Takahiro Kimata; Akiko Noda; Kohzo Nagata; Hai Jin; Guo-Ping Shi; Akihisa Iguchi; Toyoaki Murohara; and Mitsuhiro Yokota

From the Department of Cardiovascular Genome Science (X.W.C., K.O., M.S., M.Y.), Nagoya University School of Medicine, Nagoya, Japan; Departments of Geriatrics (X.W.C., M.K., K.N., E.A., H.J., A.I.), Cardiology (H.I., T.M.), and Clinical Pathophysiology (T.N.), Nagoya University Graduate School of Medicine, Nagoya, Japan; the Department of Medical Technology (T.K., A.N., K.N.), Nagoya University School of Health Sciences, Nagoya, Japan; the Department of Cardiovascular Medicine (G.-P.S.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; and the Department of Cardiology (X.W.C., H.J.), College of Medical, Yanbian University, Yanji, Jilin Province, China.

^* To whom correspondence should be addressed. E-mail: xianwu{at}med.nagoya-u.ac.jp.

Abstract--Cathepsins are cysteine proteases that participate in various types of tissue remodeling. However, their expressions during myocardial remodeling have not been examined. In this study, we investigated their expressions in the left ventricular (LV) myocardium of rats and humans with hypertension-induced LV hypertrophy or heart failure (HF). Real-time PCR and immunoblot analysis revealed that the abundance of cathepsin S mRNA or protein in the LV tissues was greater in rats or humans with HF than in those with hypertrophy or in control subjects. Immunostaining showed that cathepsin S was localized predominantly to cardiac myocytes and coronary vascular smooth muscle cells, but also overlapped in part with macrophages. Elastic lamina fragmentations significantly increased in the LV intramyocardial coronary arteries of HF rats. The amount of elastolytic activity in the extract of the LV myocardium was markedly increased for HF rats compared with controls, and this activity was mostly because of cathepsin S. Although the amount of elastin mRNA was increased in the LV myocardium of HF rats, the area of interstitial elastin was not. The expression of interleukin 1 was increased in the LV myocardium of HF rats, and this cytokine was found to increase the expression and activity of cathepsin S in cultured neonatal cardiomyocytes. These results suggest that cathepsin S participates in pathological LV remodeling associated with hypertension-induced HF. This protease is, thus, a potential target for therapeutics aimed at preventing or reversing cardiac remodeling.

Key words: myocardial remodeling • hypertension • heart failure • cysteine proteases • cardiac myocytes

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