Abstract
Epidemiological studies support a strong association between non-high-density lipoprotein cholesterol levels and heart failure incidence. The objective of the current study was to evaluate the effect of selective cholesterol lowering adeno-associated viral serotype 8 (AAV8)-mediated low-density lipoprotein receptor (LDLr) gene transfer on cardiac remodelling and myocardial oxidative stress following transverse aortic constriction (TAC) in female C57BL/6 LDLr-/- mice with mild hypercholesterolemia. Cholesterol lowering gene transfer resulted in a 65.9% (p<0.0001) reduction of plasma cholesterol levels (51.2 ± 2.2 mg/dl) compared to controls (150 ± 7 mg/dl). Left ventricular wall area was 11.2% (p<0.05) lower in AAV8-LDLr TAC mice than in control TAC mice. In agreement, pro-hypertrophic myocardial proteins were potently decreased in AAV8-LDLr TAC mice. The degree of interstitial fibrosis and perivascular fibrosis was 31.0% (p<0.001) and 29.8% (p<0.001) lower, respectively, in AAV8-LDLr TAC mice compared to control TAC mice. These structural differences were associated with improved systolic and diastolic function and decreased lung congestion in AAV8-LDLr TAC mice compared to control TAC mice. Cholesterol lowering gene therapy counteracted myocardial oxidative stress and preserved the potential for myocardial fatty acid oxidation in TAC mice. In conclusion, cholesterol lowering gene therapy attenuates pressure overload-induced heart failure in mice with mild hypercholesterolemia.
Highlights
Heart failure is the incapacity of the heart to eject blood forward at a sufficient cardiac output to meet the metabolic requirements of the body or the capacity to produce sufficient cardiac output only at the expense of pathologically elevated cardiac filling pressures or a combination of both
The objective of the current study was to evaluate the effect of selective cholesterol lowering adeno-associated viral serotype 8 (AAV8)-mediated low-density lipoprotein receptor (LDLr) gene transfer on cardiac remodelling and myocardial oxidative stress following transverse aortic constriction (TAC) in female C57BL/6 LDLr-/- mice with mild hypercholesterolemia
We have recently reported the effect of cholesterol lowering adeno-associated viral serotype 8 (AAV8)mediated low-density lipoprotein receptor (LDLr) gene therapy on cardiac function and remodelling in LDLrknockout mice kept on a diet to induce marked hypercholesterolemia (0.2% cholesterol 10% coconut oil diet) [12]
Summary
Heart failure is the incapacity of the heart to eject blood forward at a sufficient cardiac output to meet the metabolic requirements of the body (termed forward failure) or the capacity to produce sufficient cardiac output only at the expense of pathologically elevated cardiac filling pressures (termed backward failure) or a combination of both. Plasma cholesterol lowering may exert favourable effects on myocardial structure and heart function in the absence of atherosclerosis in the epicardial coronary arteries [2]. Increasing non-HDL cholesterol levels are an independent predictor of new-onset heart failure in multivariable models in Framingham Heart Study subjects that were free of coronary artery disease at the time of recruitment [3]. Detailed echocardiographic analysis of cardiac function in subjects with primary www.aging-us.com hypercholesterolemia without evidence of coronary artery disease revealed subclinical systolic and diastolic dysfunction [4]. The hypothesis that increased plasma cholesterol has a direct impact on the myocardium is supported by experimental animal investigations. Electrical remodelling of the heart [6] and systolic and diastolic dysfunction [7] were demonstrated in hypercholesterolemic rabbits in vivo. Clinical trials with proprotein convertase subtilisin/kexin type 9 inhibitors in human subjects with atherosclerotic vascular disease [10, 11] indicate that true normocholesterolemia and hypercholesterolemia in humans should be defined in terms of plasma cholesterol that are much lower than previously accepted
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