支链氨基酸在心力衰竭过程中的功能及相关研究

Heart failure is the leading cause of mortality and hospitalization in many countries and effective therapy is not yet available. Therefore understanding the pathological mechanism of heart failure and thus developing novel approaches for diagnosis and treatment of heart failure are of major significance. Our recent study has identified a novel mechanism of heart failure (unpublished). We found that BCAA catabolic system has been down-regulated during heart failure, suggesting that BCAA catabolism is likely an integrated branch of metabolic remodeling during heart failure. Using the PP2Cm knockout mice, we demonstrated that impaired BCAA catabolism promoted heart failure under pressure overload. The accumulation of BCKA triggered oxidative stress and potentially damaged mitochondria and enhanced cell death. These results suggested that down-regulation of BCAA catabolism during heart failure in turn promoted disease progression. Based on these findings, the first aim of current proposal is to unravel the underlying mechanism of BCKA mediated oxidative stress and cell death. We will investigate the impact of BCKA on mitochondrial function to elucidate how BCKA targets the Complexes of electron transfer chain which is a major source of ROS in cells. The potential role of oxidative stress in cell death will be exploited with various approaches. To extend our finding, the second aim of current proposal is to explore whether plasma level of BCAA can be used as a biochemical marker for human heart failure. Based on the information from literature and our own preliminary data, we speculate that plasma level of BCAA will increase when heart failure progresses in patients. In collaboration with our affiliated hospital, we will measure the plasma level of BCAA and associate it with cardiac parameters in heart failure patients. The third aim of current proposal is to explore potential treatments for heart failure by targeting BCAA catabolism. One nutritional approach and one pharmacological approach will be tested. Using low protein diet or a group of novel BCKD kinase inhibitors, we will examine whether heart failure progress will be decelerated by lowering BCAA level. Taken together, our research will reveal a novel function of BCAA in heart and identify new mechanisms of heart failure. More importantly, we aim to find new approaches for diagnosis and treatment of heart failure, which will have major impacts on both basic research and clinical application.

心力衰竭是严重危害国人健康与生命的重大疾病, 目前有效治疗手段缺乏，因此对心衰病理机制进行研究，发现新的诊疗方法具有重要意义。我们前期研究在国际上首次发现支链氨基酸代谢异常与心衰的发生和发展紧密相关。在野生型小鼠心衰过程中，支链氨基酸代谢受到抑制。与此同时，在我们的转基因小鼠模型中, 支链氨基酸代谢的降低促进了心衰的发展, 诱发氧化应激并加剧细胞死亡。因此病理状态下心脏中的支链氨基酸代谢异常可能会进一步促进心衰的发生和发展，形成一个正向反馈环。本课题将以这些发现为基础，深入探索支链氨基酸在心脏中调控氧化应激，促进心衰发生发展的机理。我们还将展开相关的临床研究，探讨以血清支链氨基酸作为心衰诊断的分子标记的可行性。同时我们还将检验以调节氨基酸水平为目的的药物和营养手段可否用于延缓心衰的发展。这些研究有望发现心衰发生发展的新机制，并且为心衰的诊断和治疗提供新的手段，具有重要的科学意义和社会价值。

心力衰竭是严重危害国人健康与生命的重大疾病, 目前有效治疗手段缺乏，因此对心衰病理机制进行研究，发现新的诊疗方法具有重要意义。本课题研究首次发现支链氨基酸代谢异常与心衰的发生和发展紧密相关。在野生型小鼠心衰过程中，支链氨基酸代谢酶的基因表达受到抑制，导致支链氨基酸代谢缺陷，代谢中间产物支链酮酸累积。更为重要的是，这些现象也在人的衰竭心脏中得到证实。进一步的研究发现支链氨基酸代谢酶的基因表达抑制受到转录因子ＫＬＦ１５调控。在基因敲除小鼠模型中, 支链氨基酸代谢缺陷损伤心脏的收缩功能并促进了心衰的发展。支链酮酸可以抑制线粒体氧化磷酸化，在心脏中诱发氧化应激并干扰糖脂代谢。因此病理状态下心脏中的支链氨基酸代谢异常会进一步促进心衰的发生和发展，形成一个正向恶性反馈环。利用小分子化合物纠正衰竭心脏中的支链氨基酸代谢紊乱可以有效减慢心衰发展。 心衰病人血清中支链酮酸水平的升高提示一种新的诊断方法。 因此本课题发现了心衰发生发展的新机制，为心衰的诊断和治疗提供了新的潜在靶点。