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C-type natriuretic peptide, a novel antifibrotic and antihypertrophic agent, prevents cardiac remodeling after myocardial infarction

Takeshi Soeki, MD^*, Ichiro Kishimoto, MD^*,*, Hiroyuki Okumura, MD^*, Takeshi Tokudome, MD^*, Takeshi Horio, MD, Kenji Mori, PhD^* and Kenji Kangawa, PhD^*

^* Department of Biochemistry, National Cardiovascular Center Research Institute, Suita, Osaka, Japan
Department of Medicine, National Cardiovascular Center, Suita, Osaka, Japan

Manuscript received May 28, 2004; revised manuscript received October 22, 2004, accepted October 25, 2004.

^* Reprint requests and correspondence: Dr. Ichiro Kishimoto, Department of Biochemistry, National Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan (Email: kishimot{at}ri.ncvc.go.jp).

OBJECTIVES: We assessed the hypothesis that in vivo administration of C-type natriuretic peptide (CNP) might attenuate cardiac remodeling after myocardial infarction (MI) through its antifibrotic and antihypertrophic action.

BACKGROUND: Recently, we have shown that CNP has more potent antifibrotic and antihypertrophic effects than atrial natriuretic peptide (ANP) in cultured cardiac fibroblasts and cardiomyocytes.

METHODS: Experimental MI was induced by coronary ligation in male Sprague-Dawley rats; CNP at 0.1 µg/kg/min (n = 34) or vehicle (n = 35) was intravenously infused by osmotic mini-pump starting four days after MI. Sham-operated rats (n = 34) served as controls. After two weeks of infusion, the effects of CNP on cardiac remodeling were evaluated by echocardiograpic, hemodynamic, histopathologic, and gene analysis.

RESULTS: C-type natriuretic peptide markedly attenuated the left ventricular (LV) enlargement caused by MI (LV end-diastolic dimension, sham: 6.7 ± 0.1 mm; MI+vehicle; 8.3 ± 0.1 mm; MI+CNP: 7.7 ± 0.1 mm, p < 0.01) without affecting arterial pressure. Moreover, there was a substantial decrease in LV end-diastolic pressure, and increases in dP/dt_max, dP/dt_min, and cardiac output in CNP-treated MI rats compared with vehicle-treated MI rats. Importantly, CNP infusion markedly attenuated an increase in morphometrical collagen volume fraction in the noninfarct region (sham: 3.1 ± 0.2%; MI+vehicle: 5.7 ± 0.5%; MI+CNP: 3.9 ± 0.3%, p < 0.01). In addition, CNP significantly reduced an increase in cross-sectional area of the cardiomyocytes. These effects of CNP were accompanied by suppression of MI-induced increases in collagen I, collagen III, ANP, and ß-myosin heavy chain messenger ribonucleic acid levels in the noninfarct region.

CONCLUSIONS: These data suggest that CNP may be useful as a novel antiremodeling agent.

Abbreviations and Acronyms   ANP = atrial natriuretic peptide   BNP = brain natriuretic peptide   CNP = C-type natriuretic peptide   cGMP = cyclic guanosine monophosphate   GC = guanylyl cyclase   LV = left ventricle/ventricular   MHC = myosin heavy chain   MI = myocardial infarction   PKG = cyclic guanosine monophosphate-dependent protein kinase   RV = right ventricle/ventricular   TGF = transforming growth factor

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