Cardiac Growth and Angiolensin- (1-7)

七肽血管紧张素-(1-7)[Ang-(1-7)]拮抗血管紧张素Ⅱ的升压和增殖作用，并参与血管紧张素转换酶抑制剂和AT1受体拮抗剂的降压和抗增殖作用。我们首次发现Ang-(1-7)通过激活一种新的AT(1-7)受体来抑制血管损伤后血管平滑肌细胞(VSMC)的生长和新生内膜的形成。在初步研究中，我们证明了反义寡核苷酸阻断Mas，一种被提出的Ang-(1-7)受体，逆转了Ang-(1-7)介导的导致VSMC增殖的酶途径的抑制， 提示Mas是与抗增殖反应相偶联的AT(1-7)受体。在激动人心的新研究中，我们现在报告Ang-(1-7)减少心肌细胞肥大以及心脏成纤维细胞的增殖和胶原的产生，这与已发表的研究一致，该研究表明Ang-(1-7)可以减少心肌梗死后大鼠的心肌细胞肥大，减轻心功能障碍和重塑。血管紧张素转换酶2(ACE2)是肾素-血管紧张素系统的一个新成员，由Ang II形成Ang-(1-7)，在大鼠心肌梗死后AT1受体被阻断后上调。因此，我们提出Ang-(1-7)激活MAS来反调 血管紧张素转换酶II预防心肌肥厚，减少成纤维细胞增殖和胶原生成。在具体目标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。在特定的目标2和3中，我们将确定Ang-(1-7)抑制心肌细胞肥大、心脏成纤维细胞增殖和胶原合成的分子机制。在特定的目标4中，我们将确定MAS是否介导了心肌细胞对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)在调节心肌细胞肥大、心脏成纤维细胞增殖和胶原合成中的作用，将有助于深入了解心肌肥厚和纤维化导致心功能下降导致心力衰竭的病理生理后果。

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.