TY - JOUR
T1 - Cholesterol-Lowering Gene Therapy Counteracts the Development of Non-ischemic Cardiomyopathy in Mice
AU - Muthuramu, Ilayaraja
AU - Amin, Ruhul
AU - Postnov, Andrey
AU - Mishra, Mudit
AU - Aboumsallem, Joseph Pierre
AU - Dresselaers, Tom
AU - Himmelreich, Uwe
AU - Van Veldhoven, Paul P.
AU - Gheysens, Olivier
AU - Jacobs, Frank
AU - De Geest, Bart
N1 - Funding Information:
I.M. is a postdoctoral fellow of the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen . This work was supported by Onderzoekstoelagen grant OT/13/090 of the KU Leuven and grant G0A3114N of the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen .
Publisher Copyright:
© 2017 The American Society of Gene and Cell Therapy
PY - 2017/11/1
Y1 - 2017/11/1
N2 - A causal role of hypercholesterolemia in non-ischemic heart failure has never been demonstrated. Adeno-associated viral serotype 8 (AAV8)-low-density lipoprotein receptor (AAV8-LDLr) gene transfer was performed in LDLr-deficient mice without and with pressure overload induced by transverse aortic constriction (TAC). AAV8-LDLr gene therapy resulted in an 82.8% (p < 0.0001) reduction of plasma cholesterol compared with controls. Mortality rate was lower (p < 0.05) in AAV8-LDLr TAC mice compared with control TAC mice (hazard ratio for mortality 0.457, 95% confidence interval [CI] 0.237–0.882) during 8 weeks of follow-up. AAV8-LDLr gene therapy attenuated cardiac hypertrophy, reduced interstitial and perivascular fibrosis, and decreased lung congestion in TAC mice. Cardiac function, quantified by invasive hemodynamic measurements and magnetic resonance imaging, was significantly improved 8 weeks after sham operation or after TAC in AAV8-LDLr mice compared with respective control groups. Myocardial protein levels of mammalian target of rapamycin and of acetyl-coenzyme A carboxylase were strikingly decreased following cholesterol lowering in mice without and with pressure overload. AAV8-LDLr therapy potently reduced cardiac glucose uptake and counteracted metabolic remodeling following pressure overload. Furthermore, oxidative stress and myocardial apoptosis were decreased following AAV8-LDLr therapy in mice with pressure overload. In conclusion, cholesterol-lowering gene therapy potently counteracts structural and metabolic remodeling, and enhances cardiac function. A causal role of hypercholesterolemia in non-ischemic heart failure has never been demonstrated. In this issue of Molecular Therapy, Muthuramu et al. demonstrate that AAV8-mediated cholesterol-lowering gene therapy potently counteracts structural and metabolic remodeling, and enhances cardiac function in mice with pressure overload induced by transverse aortic constriction.
AB - A causal role of hypercholesterolemia in non-ischemic heart failure has never been demonstrated. Adeno-associated viral serotype 8 (AAV8)-low-density lipoprotein receptor (AAV8-LDLr) gene transfer was performed in LDLr-deficient mice without and with pressure overload induced by transverse aortic constriction (TAC). AAV8-LDLr gene therapy resulted in an 82.8% (p < 0.0001) reduction of plasma cholesterol compared with controls. Mortality rate was lower (p < 0.05) in AAV8-LDLr TAC mice compared with control TAC mice (hazard ratio for mortality 0.457, 95% confidence interval [CI] 0.237–0.882) during 8 weeks of follow-up. AAV8-LDLr gene therapy attenuated cardiac hypertrophy, reduced interstitial and perivascular fibrosis, and decreased lung congestion in TAC mice. Cardiac function, quantified by invasive hemodynamic measurements and magnetic resonance imaging, was significantly improved 8 weeks after sham operation or after TAC in AAV8-LDLr mice compared with respective control groups. Myocardial protein levels of mammalian target of rapamycin and of acetyl-coenzyme A carboxylase were strikingly decreased following cholesterol lowering in mice without and with pressure overload. AAV8-LDLr therapy potently reduced cardiac glucose uptake and counteracted metabolic remodeling following pressure overload. Furthermore, oxidative stress and myocardial apoptosis were decreased following AAV8-LDLr therapy in mice with pressure overload. In conclusion, cholesterol-lowering gene therapy potently counteracts structural and metabolic remodeling, and enhances cardiac function. A causal role of hypercholesterolemia in non-ischemic heart failure has never been demonstrated. In this issue of Molecular Therapy, Muthuramu et al. demonstrate that AAV8-mediated cholesterol-lowering gene therapy potently counteracts structural and metabolic remodeling, and enhances cardiac function in mice with pressure overload induced by transverse aortic constriction.
KW - adeno-associated viral vectors
KW - cardiac hypertrophy
KW - cholesterol-lowering therapy
KW - gene therapy
KW - gene transfer
KW - heart failure
KW - hypercholesterolemia
KW - low-density lipoprotein receptor
KW - metabolic remodeling
KW - non-ischemic cardiomyopathy
UR - http://www.scopus.com/inward/record.url?scp=85027497403&partnerID=8YFLogxK
U2 - 10.1016/j.ymthe.2017.07.017
DO - 10.1016/j.ymthe.2017.07.017
M3 - Article
C2 - 28822689
AN - SCOPUS:85027497403
SN - 1525-0016
VL - 25
SP - 2513
EP - 2525
JO - Molecular Therapy
JF - Molecular Therapy
IS - 11
ER -