Right Heart Function in Health and Chronic Disease

 描述(由申请人提供)： 右室(RV)衰竭是心血管发病率和死亡率的普遍原因， 也是导致肺动脉高压患者死亡的主要原因。此外，右室衰竭多见于有左室功能衰竭的患者，与无右室功能不全的患者相比，右室衰竭的症状和预后明显更差。尽管有临床意义，但对RV衰竭的研究相对较少，知之甚少，需要更有效的治疗方法来治疗RV衰竭。我们报道对刺激α_1-肾上腺素能受体(α_1-AR)的变力反应在RV中是完全不同的(阴性 正性肌力)与LV(正性肌力)。重要的是，在RV衰竭时，α1-AR变力反应被上调，并从未衰竭的RV的负性变力反应切换到衰竭的RV的强健的正性变力反应。这个更新项目将建立在以下最近观察的基础上：*在两个主要的心脏α1-AR亚型(α1A和α1B)中，从α1-AR介导的非衰竭RV的负肌力向衰竭RV的正肌力的戏剧性转变仅由α1A亚型介导，而不是α1B亚型，这表明α1A亚型信号在衰竭RV中上调。在RV衰竭模型中，与α1A亚型介导的有益效果一致，治疗2wk。使用α1A亚型特异性激动剂A61603具有主要的有益效果，改善了体内功能，减少了心肌损伤(通过降低血清心肌TnI，减少心肌纤维化，以及在电子显微镜下观察到的超微结构细胞损伤)。*从机制上讲，在衰竭的RV中，活性氧(ROS)水平升高，我们的初步研究表明，对于衰竭的RV，A61603长期治疗会增加超氧化物歧化酶(SOD)的水平，并显著降低ROS。*ROS增加了细胞内两种基质金属蛋白酶-2(MMP2)的表达和活性：规范的全长MMP2(FL-MMP2)和一种新的N末端截短异构体(NTT-MMP2)。我们报道了FL-MMP2通过对肌丝的损伤来损害心肌力。相反，我们发现NTT-MMP2通过损害钙离子的处理而损害心肌力，而不损害肌丝。*A61603的慢性治疗显著降低FL-MMP2和NTT-MMP2的水平。因此，对于衰竭的RV，α1A亚型介导的FL-MMP2和NTTMMP2水平的降低可能会减少对肌丝和钙离子处理的损害。与此一致，我们发现对于衰竭的RV慢性应用A61603可以提高肌丝功能。1.假说：对于衰竭的RV，慢性α1A亚型刺激导致ROS降低，从而导致FL-MMP2和NTTMMP2水平降低，从而减少对肌丝的损伤和钙离子的处理。2.假设：在RV衰竭的慢性模型中，使用α1A亚型激动剂进行慢性治疗是有益的。目的1.确定α1A亚型治疗RV衰竭的作用机制。对于衰竭的RV，我们将确定A61603的α1A治疗的有益效果是否涉及增加超氧化物歧化酶，导致ROS减少，从而导致FL-MMP2和NTT-MMP2水平降低，从而减少对肌丝和钙离子处理的损害。目的2.在已建立的RV衰竭的慢性模型中，确定慢性α1A治疗是否对RV功能的恢复有有益影响。使用已建立的RV衰竭的慢性肺狭窄模型，我们将对小鼠进行长达20周的慢性治疗。A61603。我们将确定A61603是否能诱导RV功能的恢复和慢性RV衰竭的结局，并确定涉及的机制。

 DESCRIPTION (provided by applicant): Failure of the right ventricle (RV) is a prevalent cause of cardiovascular morbidity and mortality, and the leading cause of death in patients with pulmonary hypertension. Moreover, RV failure frequently arises in patients with failure of the left ventricle (LV) and causes markedly worse symptoms and prognosis contrasted with patients with LV failure without RV dysfunction. Despite clinical significance, RV failure is relatively understudied, poorly understood and there i a need for more effective therapies to treat RV failure. We reported that the inotropic response to stimulation of α1-adrenergic receptors (α1-ARs) is fundamentally different in the RV (negative inotropy) vs. LV (positive inotropy). Importantly, in RV failure, α1-AR inotropic responses are upregulated and switched from a negative inotropic response in non-failing RV to a robust positive inotropic response in failing RV. This renewal project will build on the following recent observations: * Of the two major cardiac α1-AR subtypes (α1A & α1B), the dramatic switch from α1-AR-mediated negative inotropy in non-failing RV to positive inotropy in failing RV is mediated solely by the α1A-subtype but not the α1B-subtype, suggesting that α1A-subtype signaling is upregulated in failing RV. Consistent with beneficial effects mediated by the α1A-subtype, in a model of RV failure, treatment for 2 wk. with the α1A-subtype-specific agonist A61603 has major beneficial effects evidenced by improved in- vivo function, and reduced myocardial injury (evidenced by lower serum cardiac TnI, less myocardial fibrosis, and less ultrastructural cellular damage observed in electron micrographs). * Mechanistically, levels of reactive oxygen species (ROS) are elevated in failing RV, and our preliminary studies show that for failing RV, chronic treatment with A61603 increased levels of superoxide dismutase (SOD) and markedly reduced ROS. * ROS increases expression and activity of two intracellular isoforms of matrix-metalloproteinase-2 (MMP-2): the canonical full-length MMP-2 (FL-MMP-2) and a novel N-terminal truncated isoform (NTT-MMP-2). We reported that FL-MMP-2 impairs myocardial force by causing damage to the myofilaments. In contrast, we found that NTT-MMP-2 impairs myocardial force by impairing Ca2+ handling, without damage to myofilaments. * Chronic treatment with A61603 markedly reduces levels of FL-MMP-2 and NTT-MMP-2. Thus, for failing RV, α1A-subtype-mediated lowering of FL-MMP-2 and NTT-MMP-2 levels may reduce damage to myofilaments and Ca2+ handling. Consistent with this, we found that for failing RV chronic treatment with A61603 increased myofilament function. 1. Hypothesis: For failing RV, chronic α1A-subtype stimulation causes reduced ROS, which leads to decreased levels of FL-MMP-2 and NTT-MMP-2, and thereby, to reduced damage to myofilaments and Ca2+ handling. 2. Hypothesis: Chronic therapy with a α1A-subtype agonist is beneficial in a chronic model of RV failure. Aim 1. Determine the mechanisms for the beneficial effects of α1A-subtype therapy in RV failure. For failing RV, we will determine if the beneficial effects of α1A therapy with A61603 involves increased SOD, leading to reduced ROS, which results in lower levels of FL-MMP-2 and NTT-MMP-2, and thereby, reduced damage to myofilaments and Ca2+ handling. Aim 2. Determine if chronic α1A therapy has a beneficial effect on recovery of RV function in a chronic model of already established RV failure. Using a chronic pulmonary stenosis model of established RV failure, we will chronically treat mice for up to 20 wk. with A61603. We will determine if A61603 induces recovery of RV function and outcomes in chronic RV failure, and determine the mechanisms involved.