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Int. J. Mol. Sci. 2017, 18(9), 2012; doi:10.3390/ijms18092012

Selective HDL-Raising Human Apo A-I Gene Therapy Counteracts Cardiac Hypertrophy, Reduces Myocardial Fibrosis, and Improves Cardiac Function in Mice with Chronic Pressure Overload

Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, Catholic University of Leuven, 3000 Leuven, Belgium
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Received: 7 August 2017 / Revised: 14 September 2017 / Accepted: 15 September 2017 / Published: 20 September 2017
(This article belongs to the Special Issue Gene Therapy)
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Abstract

Epidemiological studies support an independent inverse association between high-density lipoprotein (HDL) cholesterol levels and heart failure incidence. The effect of selective HDL-raising adeno-associated viral serotype 8-human apolipoprotein (apo) A-I (AAV8-A-I) gene transfer on cardiac remodeling induced by transverse aortic constriction (TAC) was evaluated in C57BL/6 low-density lipoprotein receptor-deficient mice. Septal wall thickness and cardiomyocyte cross-sectional area were reduced by 16.5% (p < 0.001) and by 13.8% (p < 0.01), respectively, eight weeks after TAC in AAV8-A-I mice (n = 24) compared to control mice (n = 39). Myocardial capillary density was 1.11-fold (p < 0.05) higher and interstitial cardiac fibrosis was 45.3% (p < 0.001) lower in AAV8-A-I TAC mice than in control TAC mice. Lung weight and atrial weight were significantly increased in control TAC mice compared to control sham mice, but were not increased in AAV8-A-I TAC mice. The peak rate of isovolumetric contraction was 1.19-fold (p < 0.01) higher in AAV8-A-I TAC mice (n = 17) than in control TAC mice (n = 29). Diastolic function was also significantly enhanced in AAV8-A-I TAC mice compared to control TAC mice. Nitro-oxidative stress and apoptosis were significantly reduced in the myocardium of AAV8-A-I TAC mice compared to control TAC mice. In conclusion, selective HDL-raising human apo A-I gene transfer potently counteracts the development of pressure overload-induced cardiomyopathy. View Full-Text
Keywords: high-density lipoproteins; gene therapy; cardiac hypertrophy; heart failure; pressure overload; cardiac function; oxidative stress; apolipoprotein A-I high-density lipoproteins; gene therapy; cardiac hypertrophy; heart failure; pressure overload; cardiac function; oxidative stress; apolipoprotein A-I
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MDPI and ACS Style

Amin, R.; Muthuramu, I.; Aboumsallem, J.P.; Mishra, M.; Jacobs, F.; De Geest, B. Selective HDL-Raising Human Apo A-I Gene Therapy Counteracts Cardiac Hypertrophy, Reduces Myocardial Fibrosis, and Improves Cardiac Function in Mice with Chronic Pressure Overload. Int. J. Mol. Sci. 2017, 18, 2012.

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