Mitophagic and anti-angiogenic mechanism of heart failure

描述（由申请人提供）：虽然心衰是不可避免的疾病，但其治疗取决于对衰衰心肌机制的理解。心力衰竭时，心脏经历代偿性重构（即左心室肥厚（LVH））和血管新生。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）。这导致左室壁应力持续增加，导致失效。重塑本质上意味着细胞内和细胞间基质的合成、降解和重新排列。基质金属蛋白酶（MMPs）是设计师、建筑和裁缝。该项目的长期目标是了解MMPs在心肌重构中结构和功能异质性中的差异作用。选择性MMP-2基因消融术降低生存率并加重心肌炎症引起的心力衰竭。MMP-9基因消融对心脏有保护作用。在人类心脏终末期衰竭中，MMP-9的激活取代了MMP-2的激活。该假说认为，MMP-2是组成性的，在代偿期激活蛋白酶激活受体-1 (PAR-1，一种GPCR)，并通过激活抗应激（PKB/AKT）释放生长因子。慢性应激导致线粒体自噬和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特定目的来验证：特定目的#1：确定MMP-2、PAR-1、G1s和AKT的诱导是否导致代偿性肥大，线粒体自噬是否导致MMP-9激活并降低G1s和AKT在去代偿性心力衰竭中。具体目的2：确定在代偿性重构中MMP-2是否释放血管生成生长因子，而在去代偿性心力衰竭中MMP-9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在一定程度上通过激活MMP-9，释放TIMP-3和在去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、G1s和有丝分裂在从代偿性LVH和血管生成到去代偿性LVH和抗血管生成的转换中的作用，并将对慢性心力衰竭的治疗产生影响。

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.