Molecular Mechanisms of Volume Overload

容量超载的分子机制

• 批准号: 6893056
• 负责人: Louis Dell'ltalia
• 金额: $ 52.38万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6893056
• 关键词: adrenergic receptor; angiotensin receptor; biomarker; chronic disease /disorder; disease /disorder model; dogs; enzyme activity; extracellular matrix proteins; heart disorder chemotherapy; heart function; heart ventricle; hemodynamics; human subject; human therapy evaluation; inflammation; magnetic resonance imaging; mast cell; metalloendopeptidases; mitral valve insufficiency; myocardium; patient oriented research; protein degradation; receptor binding; shear stress; sympathetic nervous system; three dimensional imaging /topography

Mitral regurgitation (MR) creates a unique hemodynamic stress by inducing a low pressure form of volume overload due to ejection into the left atrium. Chronic therapy with vasodilators reduces LV wall stress and thereby delays the need for valve replacement in aortic regurgitation; however, no such data are currently available in patients with chronic MR using standard vasodilators or agents that block the RAS. In a clinically relevant dog model of MR, we have shown increased LV ACE and chymase expression, increased LV angiotensin II (ANG II) levels, and increased mast cell numbers, but as opposed to pressure overload, there was an absence of fibrosis with net extracellular matrix (ECM) degradation. 1-adrenergic receptor blockade but not ACE inhibitor or type-1 ANG (AT1) receptor blockade, attenuated ECM degradation and improved LV remodeling and function. Our preliminary studies show also that a mast cell stabilizing drug prevented ECM degradation and improved LV function. Furthermore, there is an association between the sympathetic nervous system and myocardial production of reactive inflammatory species. We hypothesize that sympathetic nervous system activation stimulates mast cell-mediated matrix metalloproteinase activation, ECM degradation, and progressive adverse LV remodeling and failure in volume overload of MR. In Aim 1, we will show the efficacy of 1-AR blockade over AT1 receptor blockade in patients with chronic, non-surgical MR of moderate severity. We will also test the hypothesis that improved LV remodeling due to 1-AR blockade relates to a reduction in plasma markers of inflammation and collagen turnover. In Aim 2, we will test the hypothesis that extent matrix metalloproteinase activation and reactive inflammatory species production in LV myocardium of patients with surgical MR relates to the extent of LV remodeling defined by 3-dimensional magnetic resonance imaging and tissue tagging. In Aim 3, we will test the hypothesis that 1-AR blockade and mast cell stabilization independently and synergistically prevent ECM degradation by reducing LV matrix metalloprotease activation and reactive inflammatory species, resulting in improved LV remodeling and function in a clinically relevant dog model of MR.

二尖瓣反流（MR）通过诱导低压的体积超载而导致左心房中的低压形式过载，从而产生独特的血液动力学应力。血管扩张剂的慢性治疗可减轻LV壁应力，从而延迟主动脉反流中瓣膜置换的需求；但是，使用标准的血管扩张剂或阻断RAS的药物目前尚无此类数据。在MR的临床相关狗模型中，我们显示了LV ACE和CHYMASE表达增加，LV血管紧张素II（ANG II）水平增加，肥大细胞数量增加，但与压力超负荷相反，净细胞外基质（ECM）脱机没有纤维化。 1-肾上腺素能受体阻断，但没有ACE抑制剂或1型ANG（AT1）受体阻滞，减弱ECM降解并改善LV重塑和功能。我们的初步研究还表明肥大细胞 稳定药物可防止ECM降解并改善LV功能。此外，还有一个 反应性炎症物种的交感神经系统与心肌产生之间的关联。我们假设交感神经系统激活刺激了肥大细胞介导的基质金属蛋白酶激活，ECM降解以及MR的体积过载的进行性不良LV重塑和渐进性不良LV重塑和失败。在AIM 1中，我们将在AT1受体阻断中显示1-AR阻断对中等严重程度的慢性，非手术MR的患者的功效。我们还将检验以下假设：1-AR阻断引起的LV重塑改善与炎症和胶原蛋白更新的血浆标志物的减少有关。在AIM 2中，我们将检验以下假设：在具有手术MR的患者的LV心肌中基质金属蛋白酶激活和反应性炎性物种产生，与由三维磁共振成像和组织标记定义的LV重塑的程度有关。在AIM 3中，我们将测试以下假设：1-AR阻断和肥大细胞稳定稳定，并通过减少LV基质金属蛋白酶激活和反应性炎症物质来独立和协同防止ECM降解，从而改善LV重塑和功能在临床上相关的MR MR的狗模型中。