Absence of malonyl coenzyme a decarboxylase in mice increases cardiac glucose oxidation and protects the heart from ischemic injury
Absence of malonyl coenzyme a decarboxylase in mice increases cardiac glucose oxidation and protects the heart from ischemic injury
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DOI：
10.1161/circulationaha.106.642009
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发表时间：
2006-10-17
期刊：
影响因子：
37.8
通讯作者：
Lopaschuk, Gary D.
中科院分区：
文献类型：
--
作者：
Dyck, Jason R. B.;Hopkins, Teresa A.;Lopaschuk, Gary D.
急性药物抑制心脏丙二酰辅酶A脱羧酶（MCD）通过抑制脂肪酸氧化和刺激葡萄糖氧化保护心脏免受缺血性损伤。然而，目前尚不清楚慢性抑制MCD是否会导致心脏功能改变、能量代谢或缺血性cardioprotectation.Methods和Results -产生并评估MCD缺陷小鼠的体内心脏功能以及离体心脏功能、能量代谢和缺血耐受性。野生型和mcd（-/-）小鼠体内和离体心脏功能相似。来自mcd（-/-）和野生型小鼠的离体工作心脏在脂肪酸氧化、葡萄糖氧化或糖酵解速率方面没有显著差异。然而，mcd的心脏缺失导致调节脂肪酸利用的基因表达增加，这可能补偿MCD蛋白的损失，并可能导致有氧心脏中能量代谢不发生变化。尽管缺乏脂肪酸利用的变化，心脏从MCD（-/-）小鼠表现出明显的偏好，缺血后葡萄糖利用，这与一个显着的心脏保护缺血心脏从MCD（-/-）小鼠相比，野生型mice.Conclusions -删除MCD显着增加葡萄糖氧化和改善缺血后的心脏功能恢复。因此，慢性药物抑制MCD可能是治疗心肌缺血的可行方法。
Background - Acute pharmacological inhibition of cardiac malonyl coenzyme A decarboxylase (MCD) protects the heart from ischemic damage by inhibiting fatty acid oxidation and stimulating glucose oxidation. However, it is unknown whether chronic inhibition of MCD results in altered cardiac function, energy metabolism, or ischemic cardioprotection.Methods and Results - Mcd-deficient mice were produced and assessed for in vivo cardiac function as well as ex vivo cardiac function, energy metabolism, and ischemic tolerance. In vivo and ex vivo cardiac function was similar in wild-type and mcd(-/-) mice. Ex vivo working hearts from mcd(-/-) and wild-type mice displayed no significant differences in rates of fatty acid oxidation, glucose oxidation, or glycolysis. However, cardiac deletion of mcd resulted in an increased expression of genes regulating fatty acid utilization that may compensate for the loss of MCD protein and likely contributes to the absence of changes in energy metabolism in the aerobic heart. Despite the lack of changes in fatty acid utilization, hearts from mcd(-/-) mice displayed a marked preference for glucose utilization after ischemia, which correlated with a significant cardioprotection of ischemic hearts from mcd(-/-) mice compared with wild-type mice.Conclusions - Deletion of MCD markedly increases glucose oxidation and improves functional recovery of the heart after ischemia. As a result, chronic pharmacological inhibition of MCD may be a viable approach to treat myocardial ischemia.