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(Circulation. 2004;109:2143-2149.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Activation of Matrix Metalloproteinases Precedes Left Ventricular Remodeling in Hypertensive Heart Failure Rats

Its Inhibition as a Primary Effect of Angiotensin-Converting Enzyme Inhibitor

Yasushi Sakata, MD, PhD; Kazuhiro Yamamoto, MD, PhD; Toshiaki Mano, MD, PhD; Nagahiro Nishikawa, MD, PhD; Junichi Yoshida, MD, PhD; Masatsugu Hori, MD, PhD; Takeshi Miwa, PhD; Tohru Masuyama, MD, PhD

From the Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine (Y.S., K.Y., T. Mano, N.N., J.Y., M.H., T. Masuyama), and Genome Information Research Center (Y.S., T. Mano, N.N., J.Y., T. Miwa), Osaka University, Suita, Japan. Dr Masuyama is currently at the Cardiovascular Division, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.

Correspondence to Kazuhiro Yamamoto, MD, PhD, Department of Internal Medicine and Therapeutics (A8), Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita 565-0871, Japan. E-mail kazuhiro{at}medone.med.osaka-u.ac.jp

Received March 4, 2003; de novo received October 17, 2003; revision received January 6, 2004; accepted January 12, 2004.

Background— Matrix metalloproteinases (MMPs) are activated in dilated failing hearts, and angiotensin-converting enzyme (ACE) inhibition prevents left ventricular (LV) dilatation. However, it remains unclear whether activation of MMPs precedes or is secondary to LV remodeling, and an effect of ACE inhibition on MMPs is unknown.

Methods and Results— Dahl salt-sensitive rats fed a high-salt diet from 8 weeks served as the hypertensive heart failure (HF) model. LV echo, histological study, measurement of mRNA levels, and gelatin zymography were performed before (at 23 weeks) and after (at 26 weeks) the development of LV dilatation and pulmonary edema. The same procedures were conducted in the HF model rats treated with a subdepressor dose of ACE inhibitor (enalapril 5 mg · kg^–1 · d^–1) from 9 weeks. Rats fed on normal chow served as age-matched controls. In the untreated HF model rats, gene expression of MMP-2 and MMP-9 and tissue gelatinase activity were elevated at 23 weeks without LV dilatation. LV dilatation, LV systolic dysfunction, and pulmonary edema occurred at 26 weeks, with further enhancement of the expression and activity of MMPs. ACE inhibition prevented such geometrical and functional deterioration. The gene expression and activity of MMPs were suppressed by ACE inhibition at 23 weeks without a decrease in blood pressure, and the suppressive effects continued at 26 weeks.

Conclusions— MMPs are likely to trigger and promote LV remodeling, and ACE inhibition directly exerts inhibitory effect on MMPs, leading to the prevention of LV remodeling and dysfunction.

Key Words: remodeling • heart failure • hypertension

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