关键词：2008WCHD 14届世界心脏病大会 心肌缺血

      心肌缺血之间或之后，高频率的心脏脂肪酸氧化不但会降低心脏的效率，而且还会导致严重的缺血性损伤。因此，一种新型疗法通过抑制脂肪酸氧化治疗缺血性心脏病，使心脏产生能量更有效。最近，丙二酸辅酶A脱羧酶（MCD ）已被确定为一个关键酶参与了心脏日常的脂肪酸氧化。丙二酸辅酶A脱羧酶（MCD ）能够降解丙二酸辅酶A ，这是一个强有力的心脏脂肪酸氧化内源性抑制剂，同时，它还可以抑制线粒体摄取不饱和脂肪酸。如果丙二酸辅酶A脱羧酶（MCD ）的活动性受到抑制，那么丙二酸辅酶A就会增加，从而导致了脂肪酸氧化的降低。离体大鼠的心脏实验表明，丙二酸辅酶A脱羧酶（MCD ）的药理抑制剂能够提高心肌缺血后心脏的效率和功能，还可以使心脏的能量代谢由脂肪酸氧化到葡萄糖氧化。丙二酸辅酶A脱羧酶（MCD ）抑制剂类似的有益效果还体现在受需求诱导的猪在体心脏方面。在大鼠心脏进行丙二酸辅酶A脱羧酶（MCD ）基因筛除，同样可以使心肌缺血患者的心脏功能得到改进和恢复。如果来自大鼠的心脏缺乏MCD，将会使体内左前降支动脉闭塞和再灌注，心肌梗死面积的显著减小的指标同样用来与原有心脏进行比较。此外，缺乏MCD的大鼠，在其慢性心肌梗死的心衰进展过程中，功能显著降低。因此，丙二酸辅酶A脱羧酶（MCD ）抑制剂代表着一个令人振奋的治疗缺血性心脏病的新靶点。

High rates of cardiac fatty acid oxidation during and following cardiac ischemia can decrease cardiac efficiency, and can contribute to the severity of ischemic injury.  As a result, a novel therapy to treat ischemic heart disease is to inhibit fatty acid oxidation, which allows the heart to produce energy more efficiently.  Recently, malonyl CoA decarboxylase (MCD) has been identified as a key enzyme involved in the regulation of cardiac fatty acid oxidation.  MCD degrades malonyl CoA, which is a potent endogenous inhibitor of cardiac fatty acid oxidation, secondary to inhibiting mitochondrial uptake of fatty acids.  If MCD activity is inhibited malonyl CoA levels increase, resulting in a decrease in fatty acid oxidation. In the isolated working rat heart, we show that pharmacological inhibitors of MCD improve both cardiac efficiency and function post-ischemia, secondary to switching myocardial energy metabolism from fatty acid oxidation to glucose oxidation.  Similar beneficial effects of MCD inhibition are seen in the in vivo pig heart subjected to a demand-induced ischemia.  Genetic deletion of MCD from mice hearts also results in an improved recovery of heart function following ischemia.  If hearts from mice lacking MCD are subjected to an in vivo left anterior descending artery occlusion and reperfusion, a marked decrease in infarct size was also seen compared to wild type hearts.  Furthermore, the development of heart failure in chronically infarcted mouse hearts is significantly decreased in mice lacking MCD.  Hence, inhibition of MCD represents an exciting new target for the treatment of ischemic heart disease.

来自第14届世界心脏病大会
张伟译 刘琳宁校