Ussher John R, Lopaschuk Gary D
Cardiovascular Research Group, Department of Pediatrics, University of Alberta, Edmonton, Canada.
Cardiovasc Res. 2008 Jul 15;79(2):259-68. doi: 10.1093/cvr/cvn130. Epub 2008 May 22.
Cardiovascular disease is the leading cause of death and disability for people living in western societies, with ischaemic heart disease accounting for the majority of this health burden. The primary treatment for ischaemic heart disease consists of either improving blood and oxygen supply to the heart or reducing the heart's oxygen demand. Unfortunately, despite recent advances with these approaches, ischaemic heart disease still remains a major health problem. Therefore, the development of new treatment strategies is still required. One exciting new approach is to optimize cardiac energy metabolism, particularly by decreasing the use of fatty acids as a fuel and by increasing the use of glucose as a fuel. This approach is beneficial in the setting of ischaemic heart disease, as it allows the heart to produce energy more efficiently and it reduces the degree of acidosis associated with ischaemia/reperfusion. Malonyl CoA is a potent endogenous inhibitor of cardiac fatty acid oxidation, secondary to inhibiting carnitine palmitoyl transferase-I, the rate-limiting enzyme in the mitochondrial uptake of fatty acids. Malonyl CoA is synthesized in the heart by acetyl CoA carboxylase, which in turn is phosphorylated and inhibited by 5'AMP-activated protein kinase. The degradation of myocardial malonyl CoA occurs via malonyl CoA decarboxylase (MCD). Previous studies have shown that inhibiting MCD will significantly increase cardiac malonyl CoA levels. This is associated with an increase in glucose oxidation, a decrease in acidosis, and an improvement in cardiac function and efficiency during and following ischaemia. Hence, the malonyl CoA axis represents an exciting new target for the treatment of ischaemic heart disease.
心血管疾病是西方社会人群死亡和残疾的主要原因，其中缺血性心脏病占了这一健康负担的大部分。缺血性心脏病的主要治疗方法包括改善心脏的血液和氧气供应或降低心脏的氧气需求。不幸的是，尽管这些方法最近有了进展，但缺血性心脏病仍然是一个主要的健康问题。因此，仍需要开发新的治疗策略。一种令人兴奋的新方法是优化心肌能量代谢，特别是通过减少脂肪酸作为燃料的使用并增加葡萄糖作为燃料的使用。这种方法在缺血性心脏病的情况下是有益的，因为它能使心脏更有效地产生能量，并降低与缺血/再灌注相关的酸中毒程度。丙二酰辅酶A是心肌脂肪酸氧化的一种强效内源性抑制剂，它继发于抑制肉碱棕榈酰转移酶-I，这是线粒体摄取脂肪酸的限速酶。丙二酰辅酶A在心脏中由乙酰辅酶A羧化酶合成，而乙酰辅酶A羧化酶又会被5'-AMP激活的蛋白激酶磷酸化并抑制。心肌丙二酰辅酶A的降解通过丙二酰辅酶A脱羧酶（MCD）进行。先前的研究表明，抑制MCD会显著提高心脏丙二酰辅酶A水平。这与葡萄糖氧化增加、酸中毒减少以及缺血期间及之后心脏功能和效率的改善有关。因此，丙二酰辅酶A轴代表了治疗缺血性心脏病的一个令人兴奋的新靶点。
