Molecular Mechanisms of Volume Overload

容量超载的分子机制

• 批准号: 7786046
• 负责人: Louis Dell'ltalia
• 金额: $ 44.94万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7786046
• 关键词: Molecular; Mechanisms; Volume; Overload

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.

二尖瓣返流(MR)通过导致低压力形式的容量超负荷进入左心房而产生独特的血流动力学应力。血管扩张剂的长期治疗降低了左室壁压力，从而推迟了主动脉瓣反流时瓣膜置换术的需要；然而，目前还没有使用标准血管扩张剂或阻断RAS的药物的慢性MR患者的此类数据。在临床相关的MR犬模型中，我们发现左室血管紧张素转换酶和糜酶表达增加，左室血管紧张素II(Ang II)水平增加，肥大细胞数量增加，但与压力超负荷相反，没有出现纤维化和净细胞外基质(ECM)降解。阻断1-肾上腺素能受体，但不阻断血管紧张素转换酶抑制剂或1型血管紧张素转换酶(AT1)受体，可减弱ECM的降解，改善左室重构和功能。我们的初步研究还表明，肥大细胞 稳定药物可抑制ECM降解，改善左心功能。此外，还有一个 交感神经系统与心肌产生反应性炎性物质的关系。我们假设交感神经系统激活刺激肥大细胞介导的基质金属蛋白酶激活、ECM降解、进行性不良左室重构和容量超负荷衰竭。在目标1中，我们将展示1-AR受体阻滞剂对中度重度慢性非手术MR患者的疗效。我们还将验证这样的假设，即1-AR阻断导致的左室重构改善与血浆炎症标记物和胶原周转减少有关。在目标2中，我们将验证外科MR患者左室心肌中基质金属蛋白酶的激活程度和反应性炎性物质的产生程度与三维磁共振成像和组织标记所确定的左室重构程度之间的关系。在目标3中，我们将在临床相关的MR犬模型中验证1-AR阻断和肥大细胞稳定独立和协同地防止ECM降解的假设，该假说通过减少LV基质金属蛋白酶的激活和反应性炎性物质，从而改善LV重构和功能。