Cholesterol-Lowering Gene Therapy Counteracts the Development of Non-ischemic Cardiomyopathy in Mice

Abstract

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.

Effective Treatment of Diabetic Cardiomyopathy and Heart Failure with Reconstituted HDL (Milano) in Mice

“…Plasma cholesterol and lipoprotein cholesterol levels were determined using a Cholesterol Quantification kit from Sigma-Aldrich (Sigma, St. Louis, MO, USA). HDL and non-HDL lipoproteins were separated by ultracentrifugation as described [69]. Plasma triglyceride concentration was quantified using the Triglyceride Quantification kit MAK266 (Sigma, St. Louis, MO, USA) according to the instructions of the manufacturer.…”

Successful treatment of established heart failure in mice with recombinant HDL (Milano)

“…Plasma cholesterol levels were determined using a Cholesterol Quantification kit from Sigma (Sigma, St. Louis, MO, USA). HDL and non‐HDL lipoproteins were separated by ultracentrifugation as described previously (Muthuramu et al, ). Triglyceride concentration was determined in plasma using the Triglyceride Quantification kit MAK266 (Sigma‐Aldrich, Schnelldorf, Germany) according to the instructions of the manufacturer.…”

Reconstituted HDL (Milano) Treatment Efficaciously Reverses Heart Failure with Preserved Ejection Fraction in Mice

“…We have recently demonstrated that intervention with MDCO-216 reverses established pathological remodeling induced by pressure overload and constitutes a successful treatment for heart failure in mice with pressure overload [ 23 ]. Since pressure overload induced by transverse aortic constriction (TAC) leads to cardiac dilatation and HFrEF [ 24 ], the question remains whether this HDL-targeted intervention may be effective in HFpEF.…”