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

Ilayaraja Muthuramu, Ruhul Amin, Joseph Pierre Aboumsallem, Mudit Mishra, Emma Louise Robinson, Bart De Geest*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

17 Citations (Web of Science)

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.
Original languageEnglish
Pages (from-to)2028-2040
Number of pages13
JournalArteriosclerosis Thrombosis and Vascular Biology
Volume38
Issue number9
DOIs
Publication statusPublished - 1 Sep 2018

Keywords

  • apoptosis
  • constriction
  • heart failure
  • hypotension
  • oxidative stress
  • HIGH-DENSITY-LIPOPROTEIN
  • SCAVENGER RECEPTOR BI
  • II TYPE-1 RECEPTOR
  • KNOCKOUT MICE
  • A-I
  • MYOCARDIAL-INFARCTION
  • OXIDATIVE STRESS
  • RAT-LIVER
  • HDL
  • CHOLESTEROL

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