From the Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences (I.M., R.A., J.P.A., M.M., B.D.G.).
Experimental Cardiology, Department of Cardiovascular Sciences (E.L.R.), Catholic University of Leuven, Belgium.
Arterioscler Thromb Vasc Biol. 2018 Sep;38(9):2028-2040. doi: 10.1161/ATVBAHA.118.310946.
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.
目的-我们研究了以下假设：Scarb1 小鼠中的高密度脂蛋白（HDL）功能障碍会在没有和存在压力超负荷的情况下对心脏功能产生负面影响。其次，我们评估了通过肝细胞特异性 SR-BI（清道夫受体 B 类，I 型）表达后 E1E3E4 缺失腺病毒 AdSR-BI（在肝细胞中表达 SR-BI 蛋白的 E1E3E4 缺失腺病毒载体）转移对 Scarb1 小鼠的 HDL 代谢进行归一化是否可以消除全身 SR-BI 缺乏对心脏结构和功能的影响。方法和结果-在 14 周龄时进行横主动脉缩窄（TAC）或假手术，在盐水注射后 2 周或在用 AdSR-BI 或对照载体 Adnull 进行基因转移后进行 TAC。与野生型 TAC 小鼠相比，Scarb1 TAC 小鼠在 8 周的随访期间死亡率显着增加（风险比，2.02；95%CI，1.14-3.61）。在 TAC 诱导压力超负荷之前进行 2 周的肝细胞特异性 SR-BI 基因转移可显着降低 Scarb1 小鼠的死亡率（风险比，0.329；95%CI，0.180-0.600）。肝细胞特异性 SR-BI 表达消除了 Scarb1 TAC 小鼠中心肌肥大和肺充血的增加，并抵消了心肌细胞凋亡、间质和血管周围纤维化的增加。尽管 Scarb1 假手术小鼠没有检测到结构性心脏病，但它们仍表现出收缩期和舒张期功能障碍和低血压，这完全可以通过 AdSR-BI 转移来逆转。此外，AdSR-BI 转移消除了 Scarb1 TAC 小鼠的舒张末期压力增加和舒张功能障碍。肝细胞特异性 SR-BI 转移挽救了 Scarb1 小鼠中增加的氧化应激和降低的抗氧化防御系统。
