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(Circulation. 2004;110:3306-3312.)
© 2004 American Heart Association, Inc.

Coronary Heart Disease

Overexpression of Brain Natriuretic Peptide Facilitates Neutrophil Infiltration and Cardiac Matrix Metalloproteinase-9 Expression After Acute Myocardial Infarction

Rika Kawakami, MD; Yoshihiko Saito, MD, PhD; Ichiro Kishimoto, MD, PhD; Masaki Harada, MD, PhD; Koichiro Kuwahara, MD, PhD; Nobuki Takahashi, MD; Yasuaki Nakagawa, MD; Michio Nakanishi, MD; Keiji Tanimoto, MD; Satoru Usami, MD; Shinji Yasuno, MD; Hideyuki Kinoshita, MD; Hideki Chusho, MD, PhD; Naohisa Tamura, MD, PhD; Yoshihiro Ogawa, MD, PhD; Kazuwa Nakao, MD, PhD

From the Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan. Dr Saito is now at the First Department of Internal Medicine, Nara Medical University, Nara, Japan.

Correspondence to Ichiro Kishimoto, National Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka, 565-8565, Japan. E-mail kishimot{at}ri.ncvc.go.jp

Received January 4, 2004; de novo received June 8, 2004; accepted July 7, 2004.

Background— Recent clinical trials have shown that systemic infusion of nesiritide, a recombinant human brain natriuretic peptide (BNP), improves hemodynamic parameters in acutely decompensated hearts. This suggests that BNP exerts a direct cardioprotective effect and might thus be a useful therapeutic agent with which to treat acute myocardial infarction (MI). In the present study, we used BNP-transgenic (BNP-Tg) mice with elevated plasma BNP to determine whether and how BNP contributes to left ventricular remodeling and healing after MI.

Methods and Results— We examined the accumulation of neutrophils and the expression and activation of matrix metalloproteinase (MMP)-9 in the ventricles of male BNP-Tg mice and their nontransgenic (non-Tg) littermates during the early phase after acute MI. The numbers of neutrophils infiltrating the infarcted area were significantly increased in BNP-Tg mice 3 days after MI. In addition, both the gene expression and zymographic activity of MMP-9, but not MMP-2, were significantly higher in BNP-Tg than non-Tg mice. Double immunostaining revealed that neutrophils are the main source of the MMP-9, although doxycycline, an MMP inhibitor, had no effect on neutrophil infiltration of the infarcted area in BNP-Tg mice.

Conclusions— These results demonstrate that elevated plasma BNP facilitates neutrophil infiltration of the infarcted area after MI and increases the activity of the MMP-9 they produce. This suggests that BNP plays a key role in the processes of extracellular matrix remodeling and wound-healing during the early phase after acute MI.

Key Words: metalloproteinases • myocardial infarction • natriuretic peptides • remodeling • neutrophils

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