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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

View larger version (28K): [in a new window]   Figure 1 Time course of systolic blood pressure (A) and pulse rate (B) in sham-operated rats (closed triangles) and in rats with myocardial infarction (MI) before and during infusion of 0.1 µg/kg/min C-type natriuretic peptide (CNP) (closed circles) or vehicle (5% glucose solution) (open squares). Values are mean ± SEM. A p value for systolic blood pressure by two-way analysis of variance: group <0.001; time course <0.001; group/time course interaction <0.001, and a p value for pulse rate by two-way analysis of variance: group <0.05; time course <0.001; group/time course interaction <0.01. **p < 0.01, *p < 0.05 compared with the sham-operated group at same stage by Bonferroni multiple-comparison t test. BPM = beats/min.

View larger version (102K): [in a new window]   Figure 2 The effect of C-type natriuretic peptide (CNP) infusion on collagen volume fraction in the remote and border noninfarcted left ventricular area after myocardial infarction (MI). Representative photomicrographs of collagen volume stained with Sirius red in the remote noninfarcted LV (x200 magnification) (left) and quantitative morphometric analysis (right). Values are mean ± SEM. **p < 0.01 compared with the sham-operated group; ##p < 0.01 compared with the MI+vehicle group by analysis of variance and Bonferroni multiple-comparison t test.

View larger version (99K): [in a new window]   Figure 3 The effect of C-type natriuretic peptide (CNP) infusion on cardiac hypertrophy in the noninfarcted left ventricle. Representative photomicrographs of cardiomyocyte size stained with hematoxylin and eosin (x400 magnification) (left) and quantitative morphometric analysis of cardiomyocyte area and diameter (right). Values are mean ± SEM. **p < 0.01 compared with the sham-operated group; ##p < 0.01 compared with the myocardial infarction (MI) + vehicle group by analysis of variance and Bonferroni multiple-comparison t test.

View larger version (60K): [in a new window]   Figure 4 The effect of C-type natriuretic peptide (CNP) on messenger ribonucleic acid (mRNA) expression associated with cardiac remodeling after myocardial infarction (MI). (A) Typical autoradiograms of Northern blot analysis of mRNA levels in right ventricle (RV) and noninfarcted left ventricle (LV) for collagen type I, collagen type III, fibronectin, transforming growth factor-(TGF)-ß-1, atrial natriuretic peptide (ANP), ß- and -myosin heavy chain (MHC), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) at the 18th day after MI. (B) Quantitative analyses of the abundance of each gene in the RV and noninfarcted LV at the 18th day after MI (n = 10 in each group). In individual samples, each mRNA value was corrected for the GAPDH mRNA value. Levels in sham-operated rats were arbitrarily assigned a value of 1.0. Values are mean ± SEM. **p < 0.01, *p < 0.05 compared with the sham-operated group; #p < 0.05 compared with the MI+vehicle group by analysis of variance and Bonferroni multiple-comparison t test. Open bars = sham; striped bars = MI+vehicle; solid bars = MI+CNP.

View larger version (23K): [in a new window]   Figure 5 The effect of C-type natriuretic peptide (CNP) on collagen synthesis via the cyclic guanosine monophosphate (cGMP)/cyclic guanosine monophosphate-dependent protein kinase (PKG) pathway in cultured neonatal rat cardiac fibroblasts. (A and B) The effect of CNP and 8-Bromo cGMP on [3H]proline incorporation in cardiac fibroblasts. (C) [3H]proline incorporation in the presence or absence of 10–8 mol/l CNP with or without Rp-8-pCPT-cGMP, PKG inhibitor. Values are mean ± SEM. **p < 0.01, *p < 0.05 compared with control by analysis of variance and Bonferroni multiple-comparison t test.

View larger version (54K): [in a new window]   Figure 6 Endogenous C-type natriuretic peptide (CNP) expressions after myocardial infarction (MI). (A) Endogenous CNP mRNA abundance in the infarcted left ventricle (LV), noninfarcted LV, and right ventricle (RV) at different times after MI and on day 3 after sham operation. Values are mean ± SEM. **p < 0.01, *p < 0.05 compared with sham by analysis of variance and Bonferroni's multiple-comparison t test. (B) Immunofluorescent microscopic CNP expression. Upper photomicrographs show the section on day 7 after MI stained by the specific antibody against CNP-53 (left, green) and stained by antifibronectin antibody (right, red). Lower photomicrograph shows the merged image (x600 magnification). GAPDH = glyceraldehydes-3-phosphate dehydrogenase.