Proteasome activity in cardiac hypertrophy and heart failure

心脏肥大和心力衰竭中的蛋白酶体活性

• 批准号: 8055559
• 负责人: GOPAL Jegadeesh BABU
• 金额: $ 19.5万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-02 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8055559
• 关键词: Acute; Biological; Cardiac; Cardiomyopathies; Cicatrix; Clinical; Collagen; Coronary artery; Data; Degradation Pathway; Extracellular Matrix; Heart; Heart Hypertrophy; Heart failure; Hypertrophy; Metalloproteases; Methods; Molecular; Muscle Cells; Myocardial Infarction; Myocardial rupture; Phase; Physiologic intraventricular pressure; Process; Proteasome Inhibition; Proteasome Inhibitor; Proteins; Regulation; Risk; Shapes; Staging; Structure; Testing; Ventricular; Ventricular Remodeling; artery occlusion; base; clinically relevant; in vivo; mouse model; multicatalytic endopeptidase complex; novel; novel therapeutics; prevent; public health relevance

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.

描述（由申请人提供）：心肌梗死（MI）的一个可怕后果是心脏重塑，这是一个由于负荷增加、收缩力降低和神经激素调节而改变心室形状和功能的过程。在分子水平上，心室重构在很大程度上是由基质金属蛋白酶的激活调节的。我们的初步数据表明，这一过程的缺血后重塑也控制的活性蛋白酶体，降解细胞内蛋白质的主要途径。具体来说，我们发现，蛋白酶体活性增加的背景下，缺血后容量超负荷，并阻止这种激活与蛋白酶体抑制剂逆转心室重塑的细胞外基质积累，心肌细胞肥大，收缩功能丧失。这是一个新奇的、出乎意料的观察。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塑和瘢痕形成的机制。我们的总体假设是，冠状动脉闭塞后蛋白酶体激活在早期促进瘢痕形成，但从长远来看，增加胶原积累和心脏肥大，从而加速向心力衰竭的转变。我们假设，阻断这一过程将逆转缺血后重塑时，不可逆的缺血性损伤发生后应用。这一假设将通过三个具体目标进行检验。1.我们将测试蛋白酶体抑制与基质金属蛋白酶抑制相比对缺血后心室重构参数的影响。2.我们将确定心肌梗死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理学方法来抑制。总的来说，我们希望这些目标将回答以下两个问题。1.在细胞外基质、肌细胞大小和功能以及蛋白酶体组成和结构方面，可能解释所观察到的效应的机制是什么？2.基于这些机制，我们是否可以用另一种生物学和假设驱动的方法重现这种效应，例如用基因修饰的小鼠模型？从临床角度来看，这一建议可能会打开新的治疗途径，通过破译分子机制，不仅可以防止心脏重塑的进一步发展，而且更重要的是，可以扭转这种不利的过程。 公共卫生关系：心肌梗死（MI）的一个可怕后果是心脏重塑，这是一个由于负荷增加、收缩力降低和神经激素调节而改变心室形状和功能的过程。我们的初步数据表明，缺血后的重塑过程是由蛋白酶体的活性控制的，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塑和瘢痕形成的机制。从临床角度来看，这一建议可能会打开新的治疗途径，通过破译分子机制，不仅可以防止心脏重塑的进一步发展，而且更重要的是，可以扭转这种不利的过程。

项目成果

Decreased sarcolipin protein expression and enhanced sarco(endo)plasmic reticulum Ca2+ uptake in human atrial fibrillation.

• DOI: 10.1016/j.bbrc.2011.05.113
• 发表时间: 2011-06-24
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Shanmugam, Mayilvahanan;Molina, Cristina E.;Gao, Shumin;Severac-Bastide, Renaud;Fischmeister, Rodolphe;Babu, Gopal J.
• 通讯作者: Babu, Gopal J.