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AT1受体拮抗剂的降压和抗增殖作用。我们首次证明Ang-(1-7)通过激活一种新的AT（1-7）受体抑制血管损伤后血管平滑肌细胞（VSMC）的生长和新内膜的形成。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Ang-(1-7)介导的酶促途径抑制，导致VSMC增殖。

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.