Proteasome activity in cardiac hypertrophy and heart failure

描述(申请人提供)：心肌梗死(MI)的一个可怕后果是心脏重构，这是一个由于负荷增加、收缩能力降低和神经激素调节的结果而改变心室形状和功能的过程。在分子水平上，心肌重构在很大程度上受基质金属蛋白水解酶的激活调节。我们的初步数据表明，这一缺血后重塑过程也受到蛋白酶体活性的控制，蛋白酶体是细胞内蛋白质降解的主要途径。具体地说，我们发现，在缺血后容量超负荷的情况下，蛋白酶体活性增加，用蛋白酶体抑制剂阻断这种激活可以逆转细胞外基质积聚、心肌细胞肥大和收缩功能丧失方面的心室重构。这是一个新奇而出人意料的观察结果。因此，我们建议进一步探讨蛋白酶体调节心肌梗死后心脏重构和瘢痕形成的机制。我们的全球假设是，冠状动脉闭塞后蛋白酶体的激活在早期促进了瘢痕的形成，但从长远来看，会增加胶原的积累和心肌肥厚，从而加速向心力衰竭的过渡。我们假设，在发生不可逆转的缺血损伤后应用阻断这一过程将逆转缺血后的重塑。这一假设将通过三个具体目标进行检验。1.我们将比较蛋白酶体抑制和基质金属蛋白酶抑制对缺血后心室重构参数的影响。2.我们将确定心肌梗塞急性期蛋白酶体活性对瘢痕形成和心脏破裂风险的影响。3.我们将确定心脏蛋白酶体是否可以通过生物学方法而不是药物方法来抑制。综上所述，我们预计这些目标将回答以下两个问题。1.从细胞外基质、心肌细胞的大小和功能、蛋白酶体的组成和结构等方面来说，可能解释观察到的效应的机制是什么？2.基于这些机制，我们能否以一种替代的、生物学的和假设驱动的方法重现这些效应，例如用转基因小鼠模型？从临床角度来看，这一提议可能通过破译分子机制开辟新的治疗途径，这些分子机制不仅可以防止心脏重构的进一步进展，更重要的是，可以逆转这一不利过程。 公共卫生相关性：心肌梗死(MI)的一个可怕后果是心脏重构，这是一个由于负荷增加、收缩能力降低和神经激素调节的结果而改变心室形状和功能的过程。我们的初步数据表明，这一缺血后重塑过程受蛋白酶体活性的控制，蛋白酶体是细胞内蛋白质降解的主要途径。因此，我们建议进一步探讨蛋白酶体调节心肌梗死后心脏重构和瘢痕形成的机制。从临床角度来看，这一提议可能通过破译分子机制开辟新的治疗途径，这些分子机制不仅可以防止心脏重构的进一步进展，更重要的是，可以逆转这一不利过程。

DESCRIPTION (provided by applicant): A dreadful consequence of myocardial infarction (MI) is cardiac remodeling, a process modifying ventricular shape and function as a consequence of increased load, decreased contractility and neurohormonal regulation. At the molecular level, ventricular remodeling is largely modulated by the activation of matrix metalloproteases. Our Preliminary Data demonstrate that this process of post-ischemic remodeling is also controlled by the activity of the proteasome, the main pathway of degradation of intracellular proteins. Specifically, we found that proteasome activity increases in a context of post-ischemic volume overload, and that blocking such activation with proteasome inhibitors reverses ventricular remodeling in terms of extracellular matrix accumulation, myocyte hypertrophy, and loss of contractile function. This is a novel and unexpected observation. Therefore, we propose to explore further the mechanisms by which the proteasome regulates cardiac remodeling and scar formation after MI. It is our global hypothesis that proteasome activation after coronary artery occlusion promotes scar formation at the early stage but, in the long term, increases collagen accumulation and cardiac hypertrophy, and thereby accelerates the transition into heart failure. We hypothesize that blocking this process will reverse post-ischemic remodeling when applied after the occurrence of irreversible ischemic damage. This hypothesis will be tested through three Specific Aims. 1. We will test the impact of proteasome inhibition, as compared to matrix metalloproteases inhibition, on the parameters of post-ischemic ventricular remodeling. 2. We will determine the impact of proteasome activity at the acute phase of myocardial infarction in terms of scar formation and of the risk of cardiac rupture. 3. We will determine whether the cardiac proteasome can be inhibited by a biological, as opposed to pharmacological, approach. Taken together, we expect that these Aims will answer the two following questions. 1. What are the mechanisms involved, in terms of extracellular matrix, myocyte size and function, and proteasome composition and structure that may explain the observed effects? 2. Based on these mechanisms, could we reproduce such effects in an alternative, biological and hypothesis-driven approach, for example with genetically-modified mouse models? On a clinical perspective, this proposal may open novel therapeutic avenues by deciphering molecular mechanisms that could not only prevent further progression of cardiac remodeling, but also, and more importantly, that could reverse this adverse process. PUBLIC HEALTH RELEVANCE: A dreadful consequence of myocardial infarction (MI) is cardiac remodeling, a process modifying ventricular shape and function as a consequence of increased load, decreased contractility and neurohormonal regulation. Our Preliminary Data demonstrate that this process of post-ischemic remodeling is controlled by the activity of the proteasome, the main pathway of degradation of intracellular proteins. Therefore, we propose to explore further the mechanisms by which the proteasome regulates cardiac remodeling and scar formation after MI. On a clinical perspective, this proposal may open novel therapeutic avenues by deciphering molecular mechanisms that could not only prevent further progression of cardiac remodeling, but also, and more importantly, that could reverse this adverse process.