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Angiotensin-(1–7) abrogates mitogen-stimulated proliferation of cardiac fibroblasts
- Source :
- Peptides. 34:380-388
- Publication Year :
- 2012
- Publisher :
- Elsevier BV, 2012.
-
Abstract
- 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.
- Subjects :
- medicine.medical_specialty
Heart Diseases
Physiology
Cardiac fibrosis
Prostaglandin
Biochemistry
Article
Cellular and Molecular Neuroscience
chemistry.chemical_compound
Endocrinology
Internal medicine
medicine
Animals
Phosphorylation
Fibroblast
Cells, Cultured
Cell Proliferation
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Endothelin-1
biology
DNA synthesis
Angiotensin II
Myocardium
Dual Specificity Phosphatase 1
DNA
Fibroblasts
medicine.disease
Fibrosis
Peptide Fragments
Rats
medicine.anatomical_structure
Animals, Newborn
Gene Expression Regulation
chemistry
Cyclooxygenase 2
Prostaglandin-Endoperoxide Synthases
Mitogen-activated protein kinase
cardiovascular system
biology.protein
Collagen
Cyclooxygenase
Angiotensin I
Signal transduction
Signal Transduction
Subjects
Details
- ISSN :
- 01969781
- Volume :
- 34
- Database :
- OpenAIRE
- Journal :
- Peptides
- Accession number :
- edsair.doi.dedup.....edb567d6bc41ced136ffe3f32fbd600e