Intramyocardial BNP Gene Delivery Improves Cardiac Function Through Distinct Context-Dependent Mechanisms

Abstract

Background-B-type natriuretic peptide (BNP) is an endogenous peptide produced under physiological and pathological conditions mainly by ventricular myocytes. It has natriuretic, diuretic, blood pressure-lowering, and antifibrotic actions that could mediate cardiorenal protection in cardiovascular diseases. In the present study, we used BNP gene transfer to examine functional and structural effects of BNP on left ventricular (LV) remodeling. Methods and Results-Human BNP was overexpressed by using adenovirus-mediated gene delivery in normal rat hearts and in hearts during the remodeling process after infarction and in an experimental model of angiotensin II-mediated hypertension. In healthy hearts, BNP gene delivery into the anterior wall of the LV decreased myocardial fibrosis (PϽ0.01, nϭ7 to 8) and increased capillary density (PϽ0.05, nϭ7 to 8) associated with a 7.3-fold increase in LV BNP peptide levels. Overexpression of BNP improved LV fractional shortening by 22% (PϽ0.05, nϭ6 to 7) and ejection fraction by 19% (PϽ0.05, nϭ6 to 7) after infarction. The favorable effect of BNP gene delivery on cardiac function after infarction was associated with normalization of cardiac sarcoplasmic reticulum Ca 2ϩ -ATPase expression and phospholamban Thr17-phosphorylation. BNP gene delivery also improved fractional shortening and ejection fraction in angiotensin II-mediated hypertension as well as decreased myocardial fibrosis and LV collagen III mRNA levels but had no effect on angiogenesis or Ca 2ϩ -ATPase expression and phospholamban phosphorylation. Conclusions-Local intramyocardial BNP gene delivery improves cardiac function and attenuates adverse postinfarctionand angiotensin II-induced remodeling. These results also indicate that myocardial BNP has pleiotropic, contextdependent, favorable actions on cardiac function and suggest that BNP acts locally as a key mechanical load-activated regulator of angiogenesis and fibrosis. (Circ Heart Fail. 2011;4:483-495.)Key Words: B-type natriuretic peptide Ⅲ gene therapy Ⅲ heart failure Ⅲ myocardial infarction Ⅲ angiogenesis Ⅲ fibrosis H eart failure (HF) is one of the most common causes of cardiovascular morbidity and mortality, and its prevalence is rapidly increasing as the mean age of the population advances. 1 The major cause of systolic HF is coronary artery disease, whereas diastolic HF (HF with preserved ejection fraction [EF]) is more common in patients with hypertension. 2,3 Worsening of chronic systolic or diastolic dysfunction is the most common form of acute HF, accounting for a substantial number of hospitalizations with a poor prognosis. 4 A number of drugs, particularly ␤-blockers and drugs acting on the renin-angiotensin-aldosterone system, have been shown to improve survival in patients who have left ventricular (LV) systolic dysfunction. 2,3 However, identifying appropriate treatments for patients who have HF with preserved EF or acute HF has been a daunting task. [2][3][4] Clinical Perspective on p 495Atrial and B-type natriuretic peptides (ANP and BNP, re...

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“…Mice lacking the BNP gene have normal-sized hearts but increased ventricular fibrosis (Tamura et al 2000). Furthermore, local intramyocardial BNP gene delivery improves cardiac function and attenuates post-MI and Ang II-induced fibrosis and adverse remodeling (Moilanen et al 2011). The enhancement of BNP-mediated effects in the heart would thus be an attractive strategy to inhibit cardiac fibrosis.…”

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