Angiotensin-(1–7) abrogates mitogen-stimulated proliferation of cardiac fibroblasts

• Published in: Peptides (New York, N.Y. : 1980) N.Y. : 1980), 2012-04, Vol.34 (2), p.380-388
• Main Authors: McCollum, LaTronya T., Gallagher, Patricia E., Ann Tallant, E.
• Format: Article
• Language: English
• Subjects: Activated; Angiotensin I - pharmacology; Angiotensin II - pharmacology; Angiotensin-(1–7); Animals; Animals, Newborn; antagonists; binding capacity; binding sites; blood serum; Cardiac fibrosis; Cell Proliferation - drug effects; Cells, Cultured; collagen; Collagen - antagonists & inhibitors; Collagen - biosynthesis; Cyclooxygenase; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Deoxyribonucleic acid; DNA; DNA - antagonists & inhibitors; DNA - biosynthesis; Dual specificity phosphatase; Dual Specificity Phosphatase 1 - genetics; Dual Specificity Phosphatase 1 - metabolism; Endothelin-1 - pharmacology; Fibroblasts; Fibroblasts - cytology; Fibroblasts - drug effects; Fibrosis; Fibrosis - complications; Fibrosis - metabolism; Fibrosis - physiopathology; Gene Expression Regulation - drug effects; heart; Heart Diseases - complications; Heart Diseases - metabolism; Heart Diseases - physiopathology; homeostasis; Hormones; Kinases; messenger RNA; mitogen-activated protein kinase; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; Mitogen-activated protein kinases; Myocardium - cytology; Peptide Fragments - pharmacology; phosphorylation; Phosphorylation - drug effects; Prostaglandin E synthase; prostaglandin synthase; Prostaglandin-Endoperoxide Synthases - genetics; Prostaglandin-Endoperoxide Synthases - metabolism; Prostaglandins; Rats; signal transduction; Signal Transduction - drug effects; Synthesis
• ISSN: 0196-9781; 1873-5169
• DOI: 10.1016/j.peptides.2012.01.020

► Angiotensin-(1–7) [Ang-(1–7)] inhibited DNA, protein, and collagen synthesis in cardiac fibroblasts. ► Ang-(1–7) increased dual specificity phosphatase DUSP1 and reduced ERK1/ERK2 MAP kinases. ► Ang-(1–7) decreased COX-2 and prostaglandin E synthase (PGES) to reduce prostaglandins. 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 3H-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-Ala7]-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.