Mitophagic and anti-angiogenic mechanism of heart failure

描述（由申请人提供）：虽然心力衰竭是不可避免的疾病，但其管理取决于对衰竭心肌的患病机制的理解。在心力衰竭期间，心脏经历代偿性重塑（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，但血管生成下降）。这导致LV壁应力持续增加，导致失效。重塑就其本质而言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）是设计者、架构者和裁剪者。本项目的长期目标是了解MMPs在心肌重塑中的结构和功能异质性中的不同作用。选择性MMP-2基因消融降低了存活率并加重了心肌炎症诱导的心力衰竭。MMP-9基因消融具有心脏保护作用。在人类心脏终末期衰竭中，MMP-9活化取代MMP-2活化。该建议的假设是MMP-2是组成型的，并且在代偿期激活蛋白酶激活受体-1（PAR-1，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线粒体自噬以及MMP-9和MMP-13（啮齿动物中的间质胶原酶和人类中的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MMP-2、PAR-1、G1和AKT的诱导是否导致代偿性肥大，线粒体线粒体自噬是否导致MMP-9活化并减少去代偿性心力衰竭中的G1和AKT。具体目标#2：确定MMP-2是否在代偿性重塑过程中释放血管生成生长因子，MMP-9是否在去代偿性心力衰竭过程中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而部分减弱血管生成。这些研究将阐明PAR-1、MMP、TIMP、G1和线粒体自噬在从代偿性LVH和血管生成向去代偿性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。

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.