Enhancing fatty acid utilization ameliorates mitochondrial fragmentation and cardiac dysfunction via rebalancing optic atrophy 1 processing in the failing heart
Enhancing fatty acid utilization ameliorates mitochondrial fragmentation and cardiac dysfunction via rebalancing optic atrophy 1 processing in the failing heart
复制标题
增强脂肪酸利用可通过重新平衡衰竭心脏中的视神经萎缩 1 处理来改善线粒体碎片和心脏功能障碍
DOI：
10.1093/cvr/cvy052
复制
发表时间：
2018-06-01
影响因子：
10.8
通讯作者：
Gao, Feng
中科院分区：
文献类型：
--
作者：
Guo, Yongzheng;Wang, Zhen;Gao, Feng
旨在
心力衰竭（HF）的特征是与线粒体功能障碍相关的脂肪酸（FA）利用减少。最近的证据表明，提高FA的利用率可能会提供心脏保护，防止HF。我们的目的是研究心脏FA利用对压力超负荷时心脏功能的影响及其机制。
方法和结果
在C57小鼠中使用横向主动脉缩窄（TAC）来建立压力超负荷诱导的HF。与对照组相比，饲喂高脂饮食（HFD）的TAC小鼠心脏FA利用率增加，心脏功能和存活率改善。这种心脏保护作用也可以通过心脏特异性过表达CD36来提供。值得注意的是，HFD和CD36过表达都减弱了衰竭心脏中的线粒体碎片化并改善了线粒体功能。压力超负荷降低ATP依赖性金属蛋白酶（YME1L）的表达，并诱导蛋白水解裂解的动力蛋白样鸟苷三磷酸酶OPA1作为一个结果，抑制FA的利用。提高FA利用上调YME1L表达，随后重新平衡OPA1加工，导致衰竭心脏线粒体形态的恢复。此外，心脏特异性过表达YME1L对HF产生了与HFD或CD36过表达相似的心脏保护作用。
结论
这些研究结果表明，提高FA利用率通过重新平衡压力超负荷诱导的HF中的OPA1加工来改善线粒体碎片和心功能障碍，这表明了改善HF中心脏功能的独特代谢干预方法。
Aims
Heart failure (HF) is characterized by reduced fatty acid (FA) utilization associated with mitochondrial dysfunction. Recent evidence has shown that enhancing FA utilization may provide cardioprotection against HF. Our aim was to investigate the effects and the underlying mechanisms of cardiac FA utilization on cardiac function in response to pressure overload.
Methods and results
Transverse aortic constriction (TAC) was used in C57 mice to establish pressure overload-induced HF. TAC mice fed on a high fat diet (HFD) exhibited increased cardiac FA utilization and improved cardiac function and survival compared with those on control diet. Such cardioprotection could also be provided by cardiac-specific overexpression of CD36. Notably, both HFD and CD36 overexpression attenuated mitochondrial fragmentation and improved mitochondrial function in the failing heart. Pressure overload decreased ATP-dependent metalloprotease (YME1L) expression and induced the proteolytic cleavage of the dynamin-like guanosine triphosphatase OPA1 as a result of suppressed FA utilization. Enhancing FA utilization upregulated YME1L expression and subsequently rebalanced OPA1 processing, resulting in restoration of mitochondrial morphology in the failing heart. In addition, cardiac-specific overexpression of YME1L exerted similar cardioprotective effects against HF to those provided by HFD or CD36 overexpression.
Conclusions
These findings demonstrate that enhancing FA utilization ameliorates mitochondrial fragmentation and cardiac dysfunction via rebalancing OPA1 processing in pressure overload-induced HF, suggesting a unique metabolic intervention approach to improving cardiac functions in HF.