Mitophagic and anti-angiogenic mechanism of heart failure

说明(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力衰竭心肌发病机制的了解。在心力衰竭过程中，心脏经历代偿性重构(即左心室肥厚和血管新生)。不幸的是，在终末期心力衰竭期间，左心室肥厚和血管生成之间存在着不协调的现象(即左心室肥厚持续，但血管生成减少)。这会导致LV壁应力持续增加，从而导致失效。重塑本质上意味着细胞内和细胞间基质的合成、降解和重排。基质金属蛋白酶(MMPs)具有设计者、构造者和裁剪者的功能。该项目的长期目标是了解MMPs在心肌重塑的结构和功能异质性中的不同作用。选择性地去除基质金属蛋白酶-2基因降低了存活率，并加剧了由心肌炎症引起的心力衰竭。去除基质金属蛋白酶-9基因对心脏有保护作用。在人类终末期心力衰竭中，基质金属蛋白酶-9的激活取代了基质金属蛋白酶-2的激活。该方案的假设是，基质金属蛋白酶-2是结构性的，在代偿期激活蛋白酶激活的受体-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有丝分裂和基质金属蛋白酶-9和基质金属蛋白酶-13(啮齿动物的间质胶原酶和人类的基质金属蛋白酶-1)的激活。随着TIMP-3(一种凋亡/自噬因子)和抗血管生成他汀类药物的释放，这一假说将通过以下三个特定目标进行验证：特定目标#1：确定在失代偿性心力衰竭中，诱导MMP-2、PAR-1、G1s和AKT是否会导致代偿性肥厚，线粒体有丝分裂吞噬导致MMP9激活并减少G1s和AKT。具体目的#2：确定在代偿性心力衰竭的代偿性重构过程中，基质金属蛋白酶-2是否释放血管生成生长因子，以及基质金属蛋白酶-9是否释放抗血管生成的他汀类药物。具体目的#3：确定线粒体有丝分裂是否部分地通过激活基质金属蛋白酶-9、释放基质金属蛋白酶-3和在失代偿性心力衰竭时产生他汀类药物来抑制血管生成。这些研究将阐明PAR-1、MMP、TIMP、G1s和有丝分裂在从代偿性LVH和血管生成向失代偿性LVH和抗血管生成转变过程中的作用，并将对慢性心力衰竭的治疗具有重要意义。

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.