The Hypertension and Vascular Research Center, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1032, USA.
Peptides. 2012 Apr;34(2):380-8. doi: 10.1016/j.peptides.2012.01.020. Epub 2012 Feb 2.
Previous studies showed that angiotensin-(1-7) [Ang-(1-7)] attenuates cardiac remodeling by reducing both interstitial and perivascular fibrosis. Although a high affinity binding site for Ang-(1-7) was identified on cardiac fibroblasts, the molecular mechanisms activated by the heptapeptide hormone were not identified. We isolated cardiac fibroblasts from neonatal rat hearts to investigate signaling pathways activated by Ang-(1-7) that participate in fibroblast proliferation. Ang-(1-7) reduced (3)H-thymidine, -leucine and -proline incorporation into cardiac fibroblasts stimulated with serum or the mitogen endothelin-1 (ET-1), demonstrating that the heptapeptide hormone decreases DNA, protein and collagen synthesis. The reduction in DNA synthesis by Ang-(1-7) was blocked by the AT((1-7)) receptor antagonist [d-Ala(7)]-Ang-(1-7), showing specificity of the response. Treatment of cardiac fibroblasts with Ang-(1-7) reduced the Ang II- or ET-1-stimulated increase in phospho-ERK1 and -ERK2. In contrast, Ang-(1-7) increased dual-specificity phosphatase DUSP1 immunoreactivity and mRNA, suggesting that the heptapeptide hormone increases DUSP1 to reduce MAP kinase phosphorylation and activity. Incubation of cardiac fibroblasts with ET-1 increased cyclooxygenase 2 (COX-2) and prostaglandin synthase (PGES) mRNAs, while Ang-(1-7) blocked the increase in both enzymes, suggesting that the heptapeptide hormone alters the concentration and the balance between the proliferative and anti-proliferative prostaglandins. Collectively, these results indicate that Ang-(1-7) participates in maintaining cardiac homeostasis by reducing proliferation and collagen production by cardiac fibroblasts in association with up-regulation of DUSP1 to reduce MAP kinase activities and attenuation of the synthesis of mitogenic prostaglandins. Increased Ang-(1-7) or agents that enhance production of the heptapeptide hormone may prevent abnormal fibrosis that occurs during cardiac pathologies.
先前的研究表明，血管紧张素-(1-7)[Ang-(1-7)] 通过减少间质和血管周围纤维化来减轻心脏重构。尽管在心脏成纤维细胞上鉴定出了高亲和力的 Ang-(1-7) 结合位点，但该七肽激素激活的分子机制尚未确定。我们从新生大鼠心脏中分离出心脏成纤维细胞，以研究 Ang-(1-7) 激活的参与成纤维细胞增殖的信号通路。Ang-(1-7) 减少了血清或有丝分裂原内皮素-1(ET-1)刺激的心脏成纤维细胞中(3)H-胸腺嘧啶、-亮氨酸和-脯氨酸的掺入，表明该七肽激素可减少 DNA、蛋白质和胶原的合成。Ang-(1-7) 对 DNA 合成的抑制作用被 AT((1-7)) 受体拮抗剂 [d-Ala(7)]-Ang-(1-7) 阻断，表明该反应具有特异性。用 Ang-(1-7) 处理心脏成纤维细胞可减少 Ang II 或 ET-1 刺激的磷酸化 ERK1 和 ERK2 的增加。相比之下，Ang-(1-7) 增加了双特异性磷酸酶 DUSP1 的免疫反应性和 mRNA，表明该七肽激素可增加 DUSP1 以减少 MAP 激酶的磷酸化和活性。用 ET-1 孵育心脏成纤维细胞可增加环氧合酶 2(COX-2)和前列腺素合酶(PGES)mRNA，而 Ang-(1-7) 则阻止了这两种酶的增加，表明该七肽激素改变了促有丝分裂前列腺素的浓度和平衡。总的来说，这些结果表明，Ang-(1-7) 通过增加 DUSP1 的表达来减少 MAP 激酶的活性，并减弱促有丝分裂前列腺素的合成，从而参与维持心脏的内稳态，减少心脏成纤维细胞的增殖和胶原生成，并减少胶原生成。增加 Ang-(1-7) 或增强该七肽激素产生的药物可能预防心脏病变过程中发生的异常纤维化。
