Cardiomyocyte‐restricted over‐expression of C‐type natriuretic peptide prevents cardiac hypertrophy induced by myocardial infarction in mice

Abstract

Objective: Infused C-type natriuretic peptide (CNP) was recently found to play a cardioprotective role in preventing myocardial ischaemia/ reperfusion (I/R) injury and improving cardiac remodelling after myocardial infarction (MI) in rats. Our study aimed to investigate the effect of cardiomyocyte-specific CNP over-expression on I/R injury and MI in transgenic mice. Methods and results:We generated transgenic (TG) mice over-expressing CNP in cardiomyocytes. Elevated CNP expression on RNA and protein levels was demonstrated by RNase-protection assay and radioimmunoassay. Male TG mice and age-matched wild-type (WT) littermates were subjected to 1-hour global myocardial ischaemia and 23 h of reperfusion or permanent ligation of the coronary artery for 3 weeks.Infarct size did not differ between the WT and TG groups in mice subjected to I/R. In mice that underwent permanent ligation of coronary arteries, both left and right ventricular hypertrophy were prevented by CNP over-expression 3 weeks post-MI. Histological analysis revealed less necrosis, muscular degeneration and inflammation in infarcted TG mice. Impairment of cardiac function was less pronounced in transgenic animals than in the wild-type controls. Conclusions: Over-expression of CNP in cardiomyocytes does not affect I/R-induced infarct size but prevents cardiac hypertrophy induced by MI. Therefore, CNP may represent a potent therapeutic target for the treatment of patients with cardiac hypertrophy induced by myocardial infarction or other aetiology.

Natriuretic Peptides: Their Structures, Receptors, Physiologic Functions and Therapeutic Applications

“…Although NPR-B inactivation mutations in mice have not been shown to cause hypertrophy (Tamura et al 2004; Tsuji and Kunieda 2005), transgenic rats expressing a dominant negative form of NPR-B exhibit mild blood pressure-independent cardiac hypertrophy and increased heart rate (Langenickel et al 2006). In addition, CNP infusion was shown to reduce cardiac remodeling in response to experimentally induced myocardial infarction in rats, and transgenic expression of CNP improved outcomes in mice subjected to ischemia/reperfusion injury or myocardial infarction (Wang et al 2007). …”

Natriuretic Peptides in the Regulation of Cardiovascular Physiology and Metabolic Events

“…On the other hand, continuous infusion of CNP for 2 weeks in rats with experimental MI significantly reduced both cardiac hypertrophy and fibrosis 88. Furthermore, transgenic overexpression of CNP in cardiomyocytes has been shown to prevent development of LV hypertrophy post‐MI 89. The cGMP‐dependent signaling appears to be central for antifibrotic effects of CNP 88, 90.…”

Circulating Rather Than Cardiac Angiotensin-(1-7) Stimulates Cardioprotection After Myocardial Infarction

“…4,14 In brief, animals were anesthetized and artificially ventilated with a mixture of oxygen and room air through a rodent ventilator, to which 2% to 2.5% isoflurane was added for anesthesia. During surgery, animals were kept on a homeothermic blanket.…”

“…A microtip pressure transducer (Millar instruments, Houston, Tex) was placed in the right external carotid artery to measure arterial blood pressure, as described earlier. 4,14 The catheter was then advanced into the left ventricle (LV). Subsequently, baseline recordings were obtained for mean arterial pressure, heart rate, and LV systolic pressure.…”