Cardiomyocyte specific expression of Acyl-coA thioesterase 1 attenuates sepsis induced cardiac dysfunction and mortality
Cardiomyocyte specific expression of Acyl-coA thioesterase 1 attenuates sepsis induced cardiac dysfunction and mortality
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酰基辅酶A硫酯酶1的心肌细胞特异性表达可减轻脓毒症引起的心功能障碍和死亡率
DOI：
10.1016/j.bbrc.2015.10.078
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发表时间：
2015
影响因子：
3.1
通讯作者：
Wang Dao Wen
中科院分区：
文献类型：
--
作者：
Xia Congying;Dong Ruolan;Chen Chen;Wang Hong;Wang Dao Wen
心脏脂肪酸氧化（FAO）受损诱导的能量剥夺是脓毒症心功能不全的重要原因。酰基辅酶A硫酯酶1（ACOT 1）通过改变底物代谢参与调节心脏能量产生。本研究旨在阐明ACOT 1是否具有通过增强心脏FAO来改善脓毒性心肌功能障碍的潜力。心肌细胞特异性表达ACOT 1的转基因小鼠（α MHC-ACOT 1）及其野生型（WT）同窝出生的小鼠用大肠杆菌脂多糖（LPS; 5 mg/kg i. p.）6 h后采用超声心动图和血流动力学评估心肌功能。心肌细胞特异性表达ACOT 1可显著减弱LPS给药后左心室射血分数和缩短分数降低所证实的心功能恶化。与LPS处理的WT小鼠相比，α MHC-ACOT 1小鼠表现出葡萄糖利用和心脏FAO的显著增加。ACOT 1的存在激活了在LPS激发的WT小鼠中观察到的心脏过氧化物酶体增殖物激活受体α（PPARa）和过氧化物酶体增殖物激活受体γ-共激活因子-1 α（PGC 1a）信号传导的抑制。这些结果表明，ACOT 1具有潜在的治疗价值，以保护心脏免受脓毒症介导的功能障碍，可能通过激活PPARa/PGC 1a信号转导。
Compromised cardiac fatty acid oxidation (FAO) induced energy deprivation is a critical cause of cardiac dysfunction in sepsis. Acyl-CoA thioesterase 1 (ACOT1) is involved in regulating cardiac energy production via altering substrate metabolism. This study aims to clarify whether ACOT1 has a potency to ameliorate septic myocardial dysfunction via enhancing cardiac FAO. Transgenic mice with cardiomyocyte specific expression of ACOT1 (alpha MHC-ACOT1) and their wild type (WT) littermates were challenged with Escherichia coli lipopolysaccharide (LPS; 5 mg/kg i.p.) and myocardial function was assessed 6 h later using echocardiography and hemodynamics. Deteriorated cardiac function evidenced by reduction of the percentage of left ventricular ejection fraction and fractional shortening after LPS administration was significantly attenuated by cardiomyocyte specific expression of ACOT1. alpha MHC-ACOT1 mice exhibited a markedly increase in glucose utilization and cardiac FAO compared with LPS-treated WT mice. Suppression of cardiac peroxisome proliferator activated receptor alpha (PPARa) and PPAR gamma-coactivator-1 alpha (PGC1a) signaling observed in LPS-challenged WT mice was activated by the presence of ACOT1. These results suggest that ACOT1 has potential therapeutic values to protect heart from sepsis mediated dysfunction, possibly through activating PPARa/PGC1a signaling.