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

https://doi.org/10.1016/j.jacc.2004.10.067Get rights and content
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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/dtmax, dP/dtmin, 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 β-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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This work was supported, in part, by research grants from the Japanese Ministry of Education, Science, and Culture; the Japanese Ministry of Health, Labor and Welfare; the Program for Promotion of Fundamental Studies in Health Sciences of Pharmaceuticals and Medical Devices Agency; the Japan Cardiovascular Research Foundation; and the Kowa Life Science Foundation.