Hepatocyte-Specific SR-BI Gene Transfer Corrects Cardiac Dysfunction in Scarb1 -Deficient Mice and Improves Pressure Overload-Induced Cardiomyopathy

Abstract

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 hepatocyte-specific SR-BI transfer, which restores HDL metabolism.

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

“…Murine apo A-I levels were decreased following MDCO-216 administration, which has previously also been observed following MDCO-216 administration injection in another murine model [ 23 ] and after apo A-I Milano gene transfer in mice [ 31 ]. Furthermore, HDL cholesterol in scavenger receptor class B, type I (SR-BI) deficient mice are prominently increased [ 18 ]. However, these mice are characterized by cardiac dysfunction both in the presence and absence of pressure overload, which is likely due to the dysfunctional nature of HDL [ 18 ].…”

“…Furthermore, HDL cholesterol in scavenger receptor class B, type I (SR-BI) deficient mice are prominently increased [ 18 ]. However, these mice are characterized by cardiac dysfunction both in the presence and absence of pressure overload, which is likely due to the dysfunctional nature of HDL [ 18 ]. Therefore, the effect of MDCO-216 on cardiac structure, remodeling, and function should be understood in terms of global alterations of the HDL proteome and lipidome, which affect HDL function.…”

“…Furthermore, cardiac function was improved and heart failure was prevented following HDL-raising apo A-I gene transfer [ 17 ]. In contrast, dysfunctional HDL in scavenger receptor class B, type I (SR-BI) deficient mice led to more pronounced cardiac hypertrophy, to more severe pathological remodeling, to more prominent cardiac dysfunction, and to heart failure in mice with pressure overload [ 18 ].…”

Administration of apo A-I (Milano) nanoparticles reverses pathological remodelling, cardiac dysfunction, and heart failure in a murine model of HFpEF associated with hypertension

“…Previous studies from our lab provide powerful evidence that high-density lipoproteins (HDL) exert direct effects on the myocardium that are entirely independent of any effect on the epicardial coronary arteries [21][22][23][24][25] . Apolipoprotein (apo) A-I is the main apolipoprotein of HDL.…”

HDL dysfunction, function, and heart failure

“…Recent murine studies provide compelling evidence that HDL may exert direct effects on the myocardium that are completely independent of any effect on epicardial coronary arteries [6,7].…”