Cardiac Growth and Angiolensin- (1-7)

七肽血管紧张素-（1-7）[Ang-（1-7）]对抗血管紧张素（Ang）II的升压和增殖作用，并有助于ACE抑制剂和AT 1受体拮抗剂的抗高血压和抗增殖作用。我们首次发现Ang-（1-7）通过激活一种新的AT（1-7）受体抑制血管损伤后的血管平滑肌细胞（VSMC）生长和新生内膜形成。在初步研究中，我们证明反义寡核苷酸阻断mas（一种建议的Ang-（1-7）受体）可逆转Ang-（1-7）介导的导致VSMC增殖的酶途径抑制， 提示mas是与抗增殖反应偶联的AT（1-7）受体。在令人兴奋的新研究中，我们现在报道了Ang-（1-7）减少心肌细胞肥大以及心脏成纤维细胞增生和胶原蛋白产生，与已发表的研究一致，该研究显示心肌梗死（MI）后大鼠输注Ang-（1-7）后心肌细胞肥大减少，心室功能障碍和重塑减弱。在心肌梗死大鼠心脏中发现了一种新的肾素-血管紧张素系统成员，血管紧张素转换酶2（ACE 2），它从Ang II形成Ang-（1-7），当AT 1受体被阻断时，ACE 2表达上调。因此，我们认为Ang-（1-7）激活MAS以反调节血管生成， 血管紧张素II的作用，以防止心肌肥大和减少成纤维细胞增殖和胶原蛋白的生产。在具体目标1中，我们将研究ACE 2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。在具体目标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合成的分子机制。在具体目标4中，我们将确定mas是否介导心肌细胞对Ang-（1-7）的抗肥大反应和心脏成纤维细胞对Ang-（1-7）的抗增殖反应。了解Ang-（1-7）在调节肌细胞肥大和心脏成纤维细胞增殖和胶原合成中的作用将提供对心脏肥大和纤维化的病理生理学后果的深入了解，所述心脏肥大和纤维化导致心室功能降低，从而导致心力衰竭。

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.