Cardiac Growth and Angiolensin- (1-7)

心脏生长和血管紧张素- (1-7)

• 批准号: 6853105
• 负责人: Ann Ann Tallant
• 金额: $ 15.78万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6853105
• 关键词: angiogenesis; angiotensin II; angiotensin receptor; angiotensins; cardiac myocytes; cardiogenesis; cardiovascular injury; cell morphology; cell proliferation; collagen; fibroblasts; heart cell; heart enlargement; isozymes; laboratory rat; myocardial infarction; myogenesis; peptide hormone metabolism; peptidyl dipeptidase A; receptor expression; vascular smooth muscle

The heptapeptide angiotensin-(1-7) [Ang-(1-7)] opposes the pressor and proliferative effects of angiotensin (Ang) II and contributes to the anti-hypertensive and anti-proliferative actions of ACE inhibitors and AT1 receptor antagonists. We were the first to show that Ang-(1-7) inhibits vascular smooth muscle cell (VSMC) growth and neointimal formation following vascular injury, through activation of a novel AT(1-7) receptor. In preliminary studies, we demonstrate that antisense oligonucleotide blockade of mas, a proposed Ang-(1-7) receptor, reverses Ang-(1-7)-mediated inhibition of enzymatic pathways leading to VSMC proliferation, suggesting that mas is the AT(1-7) receptor coupled to the anti-proliferative response. In exciting new studies, we now report that Ang-(1-7) reduces myocyte hypertrophy as well as cardiac fibroblast hyperplasia and collagen production, in agreement with published studies showing a reduction in myocyte hypertrophy and attenuated ventricular dysfunction and remodeling following Ang-(1-7) infusion in rats post myocardial infarction (MI). A novel member of the renin-angiotensin system, angiotensin converting enzyme 2 (ACE2), which forms Ang-(1-7) from Ang II, was identified in the heart and was up-regulated when AT1 receptors were blocked in rats following a MI. Thus, we propose that Ang-(1-7) activates mas to counter-regulate the effects of Ang II to prevent myocardial hypertrophy and reduce fibroblast proliferation and collagen production. In Specific Aim 1, we will investigate the role of ACE2 and other Ang-(1-7)-forming enzymes in cardiac myocytes and cardiac fibroblasts. In Specific Aims 2 and 3, we will identify the molecular mechanisms by which Ang-(1-7) reduces myocyte hypertrophy and cardiac fibroblast proliferation and collagen synthesis. In Specific Aim 4, we will determine whether mas mediates the anti-hypertrophic response to Ang-(1-7) in cardiac myocytes and the anti-proliferative response to Ang-(1-7) in cardiac fibroblasts. An understanding of the role of Ang-(1-7) in regulating myocyte hypertrophy and cardiac fibroblast proliferation and collagen synthesis will provide insight into the pathophysiological consequences of cardiac hypertrophy and fibrosis that contribute to reduced ventricular function leading to heart failure.

七肽血管紧张素 - （1-7）[Ang-（1-7）]反对血管紧张素（ANG）II的压力和增殖作用，并有助于ACE抑制剂和AT1受体拮抗剂的抗高血压和抗增殖作用。我们是第一个表明Ang-（1-7）通过激活（1-7）受体的小说，抑制血管损伤后血管平滑肌细胞（VSMC）生长和新内膜形成的人。在初步研究中，我们证明了反义寡核苷酸对MAS（提出的Ang-（1-7）受体）的Ang-（1-7）介导的酶促抑制酶促途径，导致VSMC增殖，从而逆转ANG-（1-7）受体。 表明MAS是AT（1-7）受体与抗增殖反应耦合的受体。 In exciting new studies, we now report that Ang-(1-7) reduces myocyte hypertrophy as well as cardiac fibroblast hyperplasia and collagen production, in agreement with published studies showing a reduction in myocyte hypertrophy and attenuated ventricular dysfunction and remodeling following Ang-(1-7) infusion in rats post myocardial infarction (MI).肾素 - 血管紧张素系统的新成员是在心脏中鉴定出Ang II的Ang-（1-7）的血管紧张素转化酶2（ACE2），当MI后大鼠中AT1受体被阻断时，在心脏中鉴定出Ang-（1-7）。因此，我们提出Ang-（1-7）激活MAS以对抗 ANG II预防心肌肥大并减少成纤维细胞增殖和胶原蛋白产生的影响。在特定目标1中，我们将研究ACE2和其他Ang-（1-7）形成酶在心肌细胞和心脏成纤维细胞中的作用。在特定目标2和3中，我们将确定Ang-（1-7）减少心肌细胞肥大和心脏成纤维细胞增殖和胶原蛋白合成的分子机制。在特定的目标4中，我们将确定MAS在心肌细胞中介导对ANG-（1-7）的抗嗜性反应以及对心脏成纤维细胞中Ang-（1-7）的抗增殖反应。了解Ang-（1-7）在调节心肌细胞肥大和心脏成纤维细胞增殖和胶原蛋白合成中的作用将洞悉心脏肥大和纤维化的病理生理后果，从而有助于降低心室功能。