Hepatocyte-specific SR-BI gene transfer corrects cardiac dysfunction in scarb1-deficient mice and improves pressure overload-induced cardiomyopathy

Objective-We investigated the hypothesis that HDL (high-density lipoprotein) dysfunction in Scarb1^-/- mice negatively affects cardiac function both in the absence and in the presence of pressure overload. Second, we evaluated whether normalization of HDL metabolism in Scarb1^-/- mice by hepatocyte-specific SR-BI (scavenger receptor class B, type I) expression after E1E3E4-deleted adenoviral AdSR-BI (E1E3E4-deleted adenoviral vector expressing SR-BI protein in hepatocytes) transfer abrogates the effects of total body SR-BI deficiency on cardiac structure and function. Approach and Results-Transverse aortic constriction (TAC) or sham operation was performed at the age of 14 weeks, 2 weeks after saline injection or after gene transfer with AdSR-BI or with the control vector Adnull. Mortality rate in Scarb1^-/- TAC mice was significantly increased compared with wild-type TAC mice during 8 weeks of follow-up (hazard ratio, 2.02; 95% CI, 1.14-3.61). Hepatocyte-specific SR-BI gene transfer performed 2 weeks before induction of pressure overload by TAC potently reduced mortality in Scarb1^-/- mice (hazard ratio, 0.329; 95% CI, 0.180-0.600). Hepatocyte-specific SR-BI expression abrogated increased cardiac hypertrophy and lung congestion and counteracted increased myocardial apoptosis and interstitial and perivascular fibrosis in Scarb1^-/- TAC mice. Scarb1^-/- sham mice were, notwithstanding the absence of detectable structural heart disease, characterized by systolic and diastolic dysfunction and hypotension, which were completely counteracted by AdSR-BI transfer. Furthermore, AdSR-BI transfer abrogated increased end-diastolic pressure and diastolic dysfunction in Scarb1^-/- TAC mice. Increased oxidative stress and reduced antioxidant defense systems in Scarb1^-/- mice were rescued by AdSR-BI transfer. Conclusions-The detrimental effects of SR-BI deficiency on cardiac structure and function are nullified by hepatocytespecific SR-BI transfer, which restores HDL metabolism. Visual Overview-An online visual overview is available for this article.