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

Arterioscler Thromb Vasc Biol. 2018 Sep;38(9):2028-2040. doi: 10.1161/ATVBAHA.118.310946.

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.

Keywords: apoptosis; constriction; heart failure; hypotension; oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Blood Pressure
  • Cardiomegaly / blood
  • Cardiomegaly / genetics
  • Cardiomegaly / physiopathology
  • Cardiomegaly / therapy*
  • Cells, Cultured
  • Cholesterol, HDL / blood
  • Female
  • Fibrosis
  • Gene Expression
  • Gene Transfer Techniques*
  • Hepatocytes / metabolism*
  • Mice, Knockout
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Oxidative Stress
  • Scavenger Receptors, Class B / genetics*

Substances

  • Cholesterol, HDL
  • Scarb1 protein, mouse
  • Scavenger Receptors, Class B