Right Heart Function in Health and Chronic Disease

 描述（由申请人提供）： 右心室（RV）衰竭是心血管发病率和死亡率的普遍原因， 也是肺动脉高压患者死亡的主要原因。此外，RV衰竭经常出现在左心室（LV）衰竭的患者中，并导致与LV衰竭而无RV功能障碍的患者相比明显更差的症状和预后。尽管具有临床意义，但RV衰竭的研究相对不足，了解不多，需要更有效的治疗方法来治疗RV衰竭。我们报道了在RV（阴性）中，对α1-肾上腺素能受体（α1-AR）刺激的变力性反应是根本不同的 收缩力）与LV（正性收缩力）。重要的是，在RV衰竭中，α1-AR正性肌力反应上调，并从非衰竭RV中的负性肌力反应转变为衰竭RV中的稳健正性肌力反应。该更新项目将建立在以下最新观察结果的基础上：* 在两种主要的心脏α1-AR亚型（α1A和α1B）中，从非衰竭RV中α1-AR介导的负性肌力到衰竭RV中的正性肌力的戏剧性转变仅由α 1A亚型介导，而不是α 1B亚型，表明α 1A亚型信号在衰竭RV中上调。 与α 1A亚型介导的有益作用一致，在RV衰竭模型中，治疗2周。与α 1A亚型特异性激动剂A61603联用具有主要的有益作用，其表现为改善体内功能和减少心肌损伤（表现为较低的血清心肌肌钙蛋白I、较少的心肌纤维化和较少的电镜观察到的超微结构细胞损伤）。* 从机制上讲，RV衰竭时活性氧簇（ROS）水平升高，我们的初步研究表明，对于RV衰竭，A61603长期治疗增加了超氧化物歧化酶（SOD）水平，并显着减少了活性氧簇（ROS）。* ROS增加了两种细胞内基质金属蛋白酶-2（MMP-2）亚型的表达和活性：典型的全长MMP-2（FL-MMP-2）和一种新的N端截短亚型（NTT-MMP-2）。我们报道了FL-MMP-2通过引起肌丝损伤而损害心肌力。相反，我们发现NTT-MMP-2通过损害Ca 2+处理来损害心肌力，而不损害肌丝。* 用A61603长期治疗显著降低FL-MMP-2和NTT-MMP-2的水平。因此，对于RV衰竭，α 1A亚型介导的FL-MMP-2和NTT-MMP-2水平的降低可能减少对肌丝和Ca 2+处理的损伤。与此一致，我们发现，对于失败的RV，用A61603的慢性治疗增加了肌丝功能。 1.假设：对于RV衰竭，慢性α 1A亚型刺激导致ROS减少，这导致FL-MMP-2和NTT-MMP-2水平降低，从而减少对肌丝和Ca 2+处理的损伤。 2.假设：在RV衰竭的慢性模型中，α 1A亚型激动剂的长期治疗是有益的。目标1。确定α 1A亚型治疗在RV衰竭中的有益作用的机制。对于RV衰竭，我们将确定A61603 α1A治疗的有益作用是否涉及增加SOD，导致ROS减少，从而导致FL-MMP-2和NTT-MMP-2水平降低，从而减少对肌丝和Ca 2+处理的损伤。目标2.确定慢性α1A治疗是否对已建立的RV衰竭慢性模型的RV功能恢复具有有益作用。使用已建立的RV衰竭的慢性肺动脉狭窄模型，我们将长期治疗小鼠长达20周。关于A61603我们将确定A61603是否诱导慢性RV衰竭的RV功能和结局的恢复，并确定相关机制。

 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.