Mitophagic and anti-angiogenic mechanism of heart failure

心力衰竭的线粒体自噬和抗血管生成机制

• 批准号: 8403722
• 负责人: Suresh C. Tyagi
• 金额: $ 35.7万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-15 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403722
• 关键词: Ablation; Address; Angiography; Angiostatins; Antibodies; Apoptotic; Architecture; Attenuated; Autophagocytosis; Barium; Biological Assay; Blood Vessels; Blood flow; Cardiac; Chronic; Chronic stress; Cytoskeleton; DNA; Disease; Endostatins; Enzyme-Linked Immunosorbent Assay; Failure; Fibroblast Growth Factor; G-Protein-Coupled Receptors; Gelatinase A; Gelatinase B; Genes; Goals; Growth Factor; Heart; Heart failure; Heterogeneity; Human; Hypertrophy; In Situ Nick-End Labeling; Inflammation; Interstitial Collagenase; Lasers; Left Ventricular Hypertrophy; Left ventricular structure; Matrix Metalloproteinases; Measures; Mitochondria; Mus; Myocardial; Myocardium; Nature; Outcome; Oxygen Consumption; PAR-1 Receptor; Pathogenesis; Pathway interactions; Phase; Protein Array; Proto-Oncogene Proteins c-akt; Rodent; Role; Small Interfering RNA; Staging; Stress; Testing; Therapeutic; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-3; Tissue Inhibitor of Metalloproteinases; Transforming Growth Factor beta; Vascular Endothelial Growth Factors; Ventricular Remodeling; angiogenesis; antiangiogenesis therapy; collagenase 3; constriction; density; in vivo; inhibitor/antagonist; matrigel; public health relevance; tissue inhibitor of metalloproteinase 4

DESCRIPTION (provided by applicant): Although heart failure is inevitable disease, its management depends on the understanding of the mechanism of ailing to failing myocardium. During heart failure, the heart undergoes compensatory remodeling (i.e. left ventricle hypertrophy (LVH) and vascular angiogenesis. Unfortunately, during end-stage heart failure there is dis-coordination between the LVH and angiogenesis (i.e. LVH persists but angiogenesis declines). This leads to continue increase in LV wall stress, leading to failure. Remodeling by its very nature implies synthesis, degradation, and re-arrangement of intra and inter cellular matrix. Matrix metalloproteinases (MMPs) are designer, architecture and tailor. The long-term goal of this project is to understand the differential role of MMPs in structural and functional heterogeneity in myocardial remodeling. The selective MMP-2 gene ablation reduces survival and exacerbates cardiac failure-induced by myocardial inflammation. MMP-9 gene ablation is cardioprotective. In human heart end-stage failure MMP-9 activation supersedes the MMP-2 activation. The hypothesis of this proposal is that MMP-2 is constitutive and during compensatory phase activates proteinase activated receptor-1 (PAR-1, a GPCR) and releases growth factors via the activation of anti-stress (PKB/AKT). Chronic stress leads to mitochondrial mitophagy and activation of MMP-9 and MMP-13 (an interstitial collagenase in rodent and MMP-1 in human). TIMP-3 (an apoptotic/autophagic factor) and anti-angiogenic statins are released, The hypothesis will be tested by following three specific aims: Specific Aim #1: To determine whether the induction of MMP-2, PAR-1, G1s, and AKT causes compensatory hypertrophy and mitochondrial mitophagy causes MMP-9 activation and decreases G1s and AKT in de-compensatory heart failure. Specific Aim #2: To determine whether the MMP-2 releases angiogenic growth factors during compensatory remodeling and MMP-9 releases anti-angiogenic statins in de-compensatory heart failure. Specific Aim #3: To determine whether the mitochondrial mitophagy attenuates angiogenesis, in part, by activating MMP-9, releasing TIMP-3 and generating statins during de-compensatory heart failure. These studies will delineate the causative role of PAR-1, MMP, TIMP, G1s and mitophagy in switch from compensatory LVH and angiogenesis to de-compensatory LVH and anti-angiogenesis and will have therapeutic ramifications for chronic heart failure.

描述（由申请人提供）：虽然心力衰竭是不可避免的疾病，但其治疗取决于对心肌衰竭机制的理解。在心力衰竭期间，心脏会经历代偿性重塑（即左心室肥大（LVH）和血管生成）。不幸的是，在终末期心力衰竭期间，LVH 和血管生成之间存在不协调（即 LVH 持续存在，但血管生成下降）。这导致左心室壁应力持续增加，导致重塑本质上意味着细胞内和细胞间的合成、降解和重新排列。基质金属蛋白酶 (MMP) 是设计者、架构者和定制者 该项目的长期目标是了解 MMP 在心肌重塑中结构和功能异质性中的不同作用。心肌炎症引起的心力衰竭具有心脏保护作用，在人类心脏末期衰竭中，MMP-9 的激活取代了 MMP-2 的激活。建议认为，MMP-2 是组成型的，在补偿阶段激活蛋白酶激活受体 1（PAR-1，GPCR）并通过抗应激（PKB/AKT）的激活释放生长因子。慢性应激会导致线粒体自噬以及 MMP-9 和 MMP-13（啮齿动物的间质胶原酶和人类的 MMP-1）的激活。 TIMP-3（一种凋亡/自噬因子）和​​抗血管生成他汀类药物被释放，该假设将通过以下三个具体目标进行检验：具体目标#1：确定是否诱导 MMP-2、PAR-1、G1s、在失代偿性心力衰竭中，AKT 会导致代偿性肥大，线粒体自噬会导致 MMP-9 激活并减少 G1 和 AKT。具体目标#2：确定 MMP-2 在代偿性重构过程中是否释放血管生成生长因子，以及 MMP-9 在失代偿性心力衰竭中是否释放抗血管生成他汀类药物。具体目标#3：确定线粒体自噬是否部分通过激活 MMP-9、释放 TIMP-3 和在失代偿性心力衰竭期间产生他汀类药物来减弱血管生成。这些研究将阐明 PAR-1、MMP、TIMP、G1 和线粒体自噬在从代偿性 LVH 和血管生成向失代偿性 LVH 和抗血管生成转变中的致病作用，并将对慢性心力衰竭产生治疗影响。