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 language | English |
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Pages (from-to) | 2028-2040 |
Number of pages | 13 |
Journal | Arteriosclerosis Thrombosis and Vascular Biology |
Volume | 38 |
Issue number | 9 |
DOIs | |
Publication status | Published - 1 Sept 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