A new molecular pathway for diabetic cardiomyopathy

 描述（由申请人提供）：糖尿病性心肌病是一种心力衰竭综合征，发生在高达50%的2型糖尿病患者中，是这一大型糖尿病患者死亡率的主要原因。 人口这种心肌病的特征是舒张功能障碍伴肥厚，经常转变为严重收缩性心力衰竭。尽管其临床重要性，这种综合征的潜在基础是未知的。一个重要的线索是发病机制与高血糖症密切相关，但缺乏将高血糖症与下游病理生理事件连接的途径一直是该领域进展的障碍。我们已经发现了一个新的信号通路，它可能是这个难题的重要组成部分。已知高血压通过先前描述的转录机制诱导Txnip（硫氧还蛋白相互作用蛋白）在啮齿动物和人类心脏中的体内表达。Txnip具有几种“传统”功能，包括（a）结合并抑制硫氧还蛋白，硫氧还蛋白是反应性物质的清除剂，从而导致氧化应激;和（B）结合并灭活葡萄糖转运蛋白，葡萄糖转运蛋白在高血糖症期间起到保护机制的作用。Txnip的第三个较少研究的作用是诱导细胞凋亡，包括在心肌细胞中，这是一种可能导致糖尿病心肌病从舒张功能障碍转变为收缩性心力衰竭的事件。然而，Txnip诱导细胞凋亡的分子途径尚不清楚。在无偏见的蛋白质组学筛选中，我们发现Txnip意外地与Bax相互作用，Bax是细胞死亡的重要介质。此外，增加的Txnip水平（如在糖尿病中所见）构象激活Bax并诱导心肌细胞凋亡。此外，Txnip诱导的小鼠体内心脏细胞凋亡是Bax依赖性的。这些结果定义了Txnip-Bax通路的轮廓，该通路可能提供糖尿病性心肌病中高血糖和向收缩性心力衰竭转变之间的联系。本项目的目标是描述该通路的分子本质，并测试其在体内糖尿病心肌病中的作用。目的1评价Txnip激活Bax的三种潜在机制：（a）Txnip-Bax相互作用;（B）Txnip介导的硫氧还蛋白抑制，导致Bax的氧化翻译后修饰，导致其激活;和（c）Txnip介导的葡萄糖转运蛋白抑制，导致代谢应激和Bax介导的细胞死亡。目的2采用可诱导的、心肌细胞特异性Txnip和Bax基因敲除小鼠来测试Txnip-Bax通路在体内糖尿病心肌病中的总体意义。此外，通过基因“重建”的心脏Txnip和Bax基因敲除小鼠与信息Txnip和Bax突变体，这个目的测试的作用，具体的分子机制连接Txnip和Bax在体内糖尿病心肌病。阐明高血糖症与心肌病之间的联系将是一个非常重要的进展。此外，这些研究具有很高的创新性，因为我们提出的途径以前是未知的。由此产生的知识可能为未来糖尿病心肌病的特异性治疗提供基础。

 DESCRIPTION (provided by applicant): Diabetic cardiomyopathy is a heart failure syndrome that occurs in up to 50% of type 2 diabetics, and is a major contributor to mortality in this large population. This cardiomyopathy is characterized by diastolic dysfunction with hypertrophy that frequently transitions to gross systolic heart failure. Despite its clinical importance, the underlying basis of this syndrome is unknown. An important clue is that pathogenesis is strongly linked to hyperglycemia, but the absence of a pathway connecting hyperglycemia to downstream pathophysiological events has been a roadblock to progress in the field. We have discovered a new signaling pathway that may constitute an important piece of the puzzle. Hyperglycemia is known to induce the expression of Txnip (thioredoxin-interacting protein) in rodent and human hearts in vivo through a previously delineated transcriptional mechanism. Txnip has several "traditional" functions including (a) binding to and inhibition of thioredoxins, which are scavengers of reactive species, thereby resulting in oxidative stress; and (b) binding to and inactivation of glucose transporters, which functions as a protective mechanism during hyperglycemia. A third less studied action of Txnip is to induce apoptosis, including in cardiomyocytes, an event that could contribute to the transition from diastolic dysfunction to systolic heart failure in diabetic cardiomyopathy. However, the molecular pathway by which Txnip induces apoptosis is not known. In an unbiased proteomics screen, we found that Txnip unexpectedly interacts with Bax, an important mediator of cell death. Further, increased Txnip levels (as would be seen in diabetes) conformationally activate Bax and induce apoptosis in cardiomyocytes. Moreover, Txnip-induced apoptosis in the mouse heart in vivo is Bax- dependent. These results define the outlines of a Txnip-Bax pathway that may provide a link between hyperglycemia and the transition to systolic heart failure in diabetic cardiomyopathy. The goals of this project are to delineate the molecular nature of this pathway and to test its rol in diabetic cardiomyopathy in vivo. Aim 1 evaluates three potential mechanisms by which Txnip activates Bax: (a) the Txnip-Bax interaction; (b) Txnip-mediated inhibition of thioredoxins, resulting in oxidative post-translational modifications of Bax that cause its activation; and (c) Txnip-mediated inhibition of glucose transporters resulting in metabolic stress and Bax-mediated cell death. Aim 2 employs inducible, cardiomyocyte-specific Txnip and Bax knockout mice to test the overall significance of the Txnip-Bax pathway in diabetic cardiomyopathy in vivo. In addition, by genetically "reconstituting" the hearts of Txnip and Bax knockout mice with informative Txnip and Bax mutants, this aim tests the roles of the specific molecular mechanisms linking Txnip and Bax in diabetic cardiomyopathy in vivo. Elucidation of a pathway connecting hyperglycemia to cardiomyopathy would be a highly significant advance. Moreover, these studies possess high innovation as the pathway we are proposing was not previously known. The resulting knowledge may provide a basis for future specific therapies for diabetic cardiomyopathy.