CVD protection mechanisms involving ACE2/Ang-(1-7) axis

涉及ACE2/Ang-(1-7)轴的CVD保护机制

• 批准号: 8048354
• 负责人: MICHAEL J KATOVICH
• 金额: $ 56.51万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-01 至 2016-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8048354
• 关键词: Angiopoietin-2; Angiotensin II; Animals; Attenuated; Blood Vessels; Bone Marrow; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Caring; Cell Therapy; Cell physiology; Cells; Chronic; Clinical; Clinical Research; Clinical Trials; Coronary; Coronary Arteriosclerosis; Coronary artery; Coupled; Data; Development; Diabetes Mellitus; Doxorubicin; Equilibrium; Event; Fibrosis; Functional disorder; Gene Transfer; Genetic; Heart; Heart Diseases; Heart failure; Homeostasis; Homing; Human; Hypertension; Hypertrophy; Immune; Inflammatory; Infusion procedures; Injury; Investigation; Lead; Length; Ligation; Literature; Lung; Modeling; Morbidity - disease rate; Muscle Cells; Myocardial Infarction; Myocardial dysfunction; Natural regeneration; Obesity; Outcome; Patients; Peptidyl-Dipeptidase A; Pharmacotherapy; Phase; Play; Positioning Attribute; Prevalence; Prevention; Rattus; Renin-Angiotensin System; Risk Factors; Role; Signal Transduction; Site; Smoking; Smooth Muscle Myocytes; Stem cells; Testing; Therapeutic; Thrombosis; Thrombus; Toxic effect; Vascular Smooth Muscle; Vascular remodeling; Vascularization; angiotensin I (1-7); base; chemotherapy; genetically modified cells; improved; improved functioning; injured; innovation; member; mortality; multidisciplinary; neovascularization; novel; overexpression; prevent; progenitor; protective effect; receptor; repaired; success; therapeutic gene; translational approach; translational study; vasculogenesis

DESCRIPTION (provided by applicant): Heart disease (HD) remains a leading cause of morbidity and mortality despite recent advances in pharmacotherapy and improved care. Mounting prevalence of risk factors such as hypertension, obesity, and diabetes, coupled with genetic factors and smoking, have all contributed to perturbation of vascular mechanisms leading to coronary endothelial and vascular smooth muscle cell dysfunction, intimal thickening, plaque formation, vascular and cardiac remodeling, myocardial infarction, hypertrophy, and heart failure. It has been proposed that an imbalance between vasoconstrictive and vasodialator mechanisms initiated by coronary endothelial dysfunction plays a critical role in the inducing cascade of signaling events leading to pathophysiology associated with HD. Based on four years of our investigation, our preliminary data, and evidence from literature, we propose that a balance between endothelial angiotensin converting enzyme (ACE) and ACE2 is critical in maintaining normal cardiac homeostasis. Thus, an imbalance in ACE/ACE2 is central in the initiation of pathophysiological events leading to HD. We hypothesize that increasing levels of cardiac ACE2 or its product, Angiotensin-(1-7) [Ang-(1-7)], would increase coronary neovascularization, decrease cardiac remodeling, and improve cardiac function to ameliorate and reverse HD. We propose the following specific aims to support or refute this hypothesis: Aim 1 is proposed to investigate the beneficial effects of a novel and newly discovered ACE2 activator, Diminazene Aceturate (DIZE), on cardiac pathophysiology and elucidate its mechanism of action. Aim 2 will test the hypothesis that local delivery of ACE2 or Ang-(1-7) by bone marrow-derived progenitor cells (BMPCs) will reverse cardiac pathophysiology. Aim 3 will investigate the hypothesis that local delivery of ACE2 or Ang-(1-7) by human BMPCs and cardiac progenitor cells will reverse cardiac dysfunctions in immune-deficient SCID rats. This multidisciplinary, integrative, and translational approach to investigate the hypothesis that endothelial ACE/ACE2 is critical in HD pathophysiology is technically and conceptually innovative. Thus, the proposed study will: (i) provide experimental evidence for our hypothesis, (ii) establish mechanisms by which ACE2/Ang- (1-7) axis of the renin-angiotensin system produces cardiovascular protective effects, (iii) "backward- translational" studies will identify dysfunctional mechanisms in cardiovascular-relevant progenitor cells from HD patients, and (iv) put us in an outstanding position to transition into clinical phase to test both DIZE and genetically-modified cell based therapy for HD. Finally, we believe that the outcome of our investigation will have an immediate impact in providing cardioprotection in patients undergoing anthracyclin chemotherapy. PUBLIC HEALTH RELEVANCE: Endothelial dysfunction is one of the early cellular events in the development and establishment of cardiovascular diseases leading to devastating outcomes such as coronary artery disease, thrombosis, myocardial infarction, hypertrophy, and heart failure. The overall objective of our investigation is to test a novel and innovative hypothesis that an imbalance in the vasodeleterious axis (ACE/Ang II/AT1R) and vasoprotective axis (ACE2/Ang-(1-7)/MasR) of the renin-angiotensin system initiates a cascade of signaling events that result in endothelial dysfunction and lead to heart disease. Thus, we propose that restoring this imbalance by a novel ACE2 activator or by genetically-modified stem cells to deliver ACE2 or Ang-(1-7) to the site of cardiac injury, would increase vasculogenesis, and protect and regenerate cardiac myocytes leading to a long-term beneficial outcome in HD. Finally, we believe that ACE2/Ang-(1-7) based concept will have an immediate impact not only in HD therapeutics, but will lead to the development of novel cardioprotective strategies in patients undergoing anthracyclin chemotherapy.

描述（由申请人提供）：尽管最近在药物治疗和护理方面取得了进展，但心脏病（HD）仍然是发病和死亡的主要原因。高血压、肥胖和糖尿病等危险因素的患病率不断上升，加上遗传因素和吸烟，都导致血管机制受到干扰，导致冠状动脉内皮和血管平滑肌细胞功能障碍、内膜增厚、斑块形成、血管和心脏重塑、心肌梗塞、肥厚和心力衰竭。有人提出，由冠状动脉内皮功能障碍引发的血管收缩和血管舒张机制之间的不平衡在诱导信号事件级联导致与 HD 相关的病理生理学方面发挥着关键作用。根据我们四年的调查、初步数据和文献证据，我们提出内皮血管紧张素转换酶 (ACE) 和 ACE2 之间的平衡对于维持正常的心脏稳态至关重要。因此，ACE/ACE2 的不平衡是引发 HD 病理生理事件的核心。我们假设增加心脏 ACE2 或其产物血管紧张素-(1-7) [Ang-(1-7)] 的水平会增加冠状动脉新生血管形成，减少心脏重塑，并改善心脏功能，从而改善和逆转 HD。我们提出以下具体目标来支持或反驳这一假设： 目标 1 旨在研究新发现的 ACE2 激活剂 Diminazene Aceturate (DIZE) 对心脏病理生理学的有益影响，并阐明其作用机制。目标 2 将检验以下假设：骨髓源性祖细胞 (BMPC) 局部递送 ACE2 或 Ang-(1-7) 将逆转心脏病理生理学。目标 3 将研究以下假设：人类 BMPC 和心脏祖细胞局部递送 ACE2 或 Ang-(1-7) 将逆转免疫缺陷 SCID 大鼠的心脏功能障碍。这种多学科、综合性和转化性的方法来研究内皮 ACE/ACE2 在 HD 病理生理学中至关重要的假设，在技术和概念上都是创新的。因此，拟议的研究将：（i）为我们的假设提供实验证据，（ii）建立肾素-血管紧张素系统的ACE2/Ang-（1-7）轴产生心血管保护作用的机制，（iii）“向后” -“转化”研究将确定 HD 患者心血管相关祖细胞的功能障碍机制，并且 (iv) 使我们处于有利地位，可以过渡到临床阶段，以测试 DIZE 和基于基因修饰的 HD 细胞疗法。最后，我们相信我们的研究结果将对接受蒽环类化疗患者的心脏保护产生直接影响。 公共卫生相关性：内皮功能障碍是心血管疾病发生和形成的早期细胞事件之一，可导致冠状动脉疾病、血栓形成、心肌梗死、肥厚和心力衰竭等破坏性后果。我们研究的总体目标是测试一个新颖且创新的假设，即肾素-血管紧张素的血管损害轴 (ACE/Ang II/AT1R) 和血管保护轴 (ACE2/Ang-(1-7)/MasR) 不平衡系统启动一系列信号事件，导致内皮功能障碍并导致心脏病。因此，我们建议通过一种新型 ACE2 激活剂或通过基因修饰干细胞将 ACE2 或 Ang-(1-7) 递送至心脏损伤部位来恢复这种不平衡，将增加血管生成，并保护和再生心肌细胞，从而导致HD 的长期有益结果。最后，我们相信基于 ACE2/Ang-(1-7) 的概念不仅会对 HD 治疗产生直接影响，而且将导致接受蒽环类化疗患者的新型心脏保护策略的开发。