Carvedilol prevents cardiac hypertrophy and overexpression of hypoxia-inducible factor-1α and vascular endothelial growth factor in pressure-overloaded rat heart

Abstract

The use of beta-blockers has emerged as a beneficial treatment for cardiac hypertrophy. Hypoxia-inducible factor-1alpha (HIF-1alpha) is tightly regulated in the ventricular myocardium. However, the expression of HIF-1alpha in cardiac hypertrophy due to pressure overload and after treatment with beta-blocker is little known. To evaluate the effect of carvedilol on both myocardial HIF-1alpha expression and cardiac hypertrophy, infra-renal aortic banding was performed for 4 weeks in adult Sprague-Dawley rats to induce cardiac hypertrophy. Carvedilol at 50 mg/kg body weight per day after surgery was given. Heart weight and the ratio of heart weight and body weight increased significantly after aortic banding for 4 weeks in the absence of drug treatment. Mean arterial pressure increased from 80 +/- 9 mmHg in the sham group to 94 +/-5 mmHg (p < 0.001) in the banding group. Echocardiography showed concentric hypertrophy after aortic banding. Mean arterial pressure decreased after treatment with carvedilol. The increased wall thickness and heart weight was reversed to normal by carvedilol. Western blot showed that HIF-1alpha, vascular endothelial growth factor (VEGF) and brain natriuretic peptide (BNP) proteins were up-regulated and nerve growth factor-beta (NGF-beta) down-regulated in the banding group. Treatment with valsartan, doxazosin, or N-acetylcysteine did not significantly affect HIF-1alpha and VEGF proteins expression in the banding groups. Real-time polymerase chain reaction showed that mRNA of HIF-1alpha, VEGF and BNP increased and mRNA of NGF-beta decreased in the banding group. Treatment with carvedilol reversed both protein and mRNA of HIF-1alpha, VEGF, BNP, and NGF-beta to the baseline values. Increased immunohistochemical labeling of HIF-1alpha, VEGF, and BNP in the ventricular myocardium was observed in the banding group and carvedilol again normalized the labeling. In conclusion, HIF-1alpha, VEGF, and BNP mRNA and protein expression were up-regulated, while NGF-beta mRNA and protein was downregulated in the rat model of pressure-overloaded cardiac hypertrophy. Treatment with carvedilol is associated with a reversal of abnormal regulation of HIF-1alpha, VEGF, BNP, and NGF-beta in the hypertrophic myocardium.

Vascular Endothelial Growth Factor Blockade Promotes the Transition From Compensatory Cardiac Hypertrophy to Failure in Response to Pressure Overload

“…Consistent with previous results, 29,30 TAC led to a 2.9-fold (PϽ0.01) increase in VEGF-A transcript expression ( Figure 1A). To investigate the links between coronary vasculature and compensatory cardiac hypertrophy, an adenoviral vector encoding a decoy VEGF receptor fused to the Fc fragment of IgG2a (Ad-Flk) or a control vector expressing only the Fc fragment (Ad-cont) was delivered to mice, and hearts were subjected to sham surgery or pressure overload resulting from TAC.…”

“…Previous studies have shown that VEGF is upregulated in myocardium in pathological conditions such as myocardial infarction, 31,32 pressure overload, 29,30 and hemodynamic overload. 33 In vitro, it has been shown that VEGF is secreted from cardiomyocytes in response to various extracellular stimuli.…”

Copper reverses cardiomyocyte hypertrophy through vascular endothelial growth factor-mediated reduction in the cell size

“…VEGF has been extensively studied regarding its effect on cell growth and proliferation. In the cardiomyocytes, VEGF also is required for cell growth [22][23][24]. Studies in vivo have shown that a decoy VEGF receptor blocked cardiac growth induced by Akt1 activation [4,16].…”

PET imaging of cardiac hypoxia: Opportunities and challenges

“…This decreased vascularity in hypertrophic myocardium is exacerbated by increases in myocyte size and tissue fibrosis, which increase diffusion distances and decrease oxygen availability to myocytes (and perhaps more importantly, their mitochondria) [27,28]. While up-regulation of hypoxia inducible factor HIF-1α is increasingly being recognized as an important instigator of cardiac hypertrophy [29][30][31] and mediator of decline into heart failure [32][33][34], we have found no reports that successfully demonstrate non-invasive measurement of hypoxia itself in hypertrophic or failing myocardium. As we shall discuss, this is most probably because most existing approaches designed to assess tissue hypoxia have insufficient sensitivity to detect the less extreme levels of hypoxia that are likely to be involved.…”

“…Since the main mediator of hypoxic injury in the pathogenesis of cardiac hypertrophy is upregulated HIF-1α expression, HIF-1α up-regulation would seem to be the most appropriate parallel biomarker to target [29][30][31].…”