Abstract
Angiotensin (Ang) II contributes to the formation and development of myocardial fibrosis. Ghrelin, a gut peptide, has demonstrated beneficial effects against cardiovascular disease. In the present study, we explored the effect and related mechanism of Ghrelin on myocardial fibrosis in Ang II-infused rats. Adult Sprague-Dawley (SD) rats were divided into 6 groups: Control, Ang II (200ng/kg/min, microinfusion), Ang II+Ghrelin (100 μg/kg, subcutaneously twice daily), Ang II+Ghrelin+GW9662 (a specific PPAR-γ inhibitor, 1 mg/kg/d, orally), Ang II+GW9662, and Ghrelin for 4 wks. In vitro, adult rat cardiac fibroblasts (CFs) were pretreated with or without Ghrelin, Ghrelin+GW9662, or anti-Transforming growth factor (TGF)-β1 antibody and then stimulated with or without Ang II (100 nmol/L) for 24 h. Ang II infusion significantly increased myocardial fibrosis, expression of collagen I, collagen III, and TGF-β1, as well as TGF-β1 downstream proteins p-Smad2, p-Smad3, TRAF6, and p-TAK1 (all p<0.05). Ghrelin attenuated these effects. Similar results were seen in Ang II-stimulated rat cardiac fibroblasts in vitro. In addition, Ghrelin upregulated PPAR-γ expression in vivo and in vitro, and treatment with GW9662 counteracted the effects of Ghrelin. In conclusion, Ghrelin ameliorated Ang II-induced myocardial fibrosis by upregulating PPAR-γ and in turn inhibiting TGF-β1signaling.
Highlights
Myocardial fibrosis, a principal pathological basis of ventricular remodeling, is characterized by cardiac fibroblasts (CFs) proliferation and extracellular matrix deposition
The Transforming growth factor (TGF)-β1 signaling pathway is activated in myocardium and cardiac fibroblasts of rats induced by Ang II [4]
We demonstrated that Ghrelin plays an antifibrotic role in vivo and in vitro by upregulating PPAR-γ and inhibiting TGF-β1 signaling
Summary
Myocardial fibrosis, a principal pathological basis of ventricular remodeling, is characterized by CFs proliferation and extracellular matrix deposition. Ang II is a major active component in the renin-angiotensin-aldosterone system and an important stimulating factor of myocardial fibrosis in a variety of cardiovascular diseases. Ang II activation plays an important role in the proliferation, differentiation, and migration of CFs and collagen synthesis by which it contributes to the participation in the formation of myocardial fibrosis [3]. The TGF-β1 signaling pathway is activated in myocardium and cardiac fibroblasts of rats induced by Ang II [4]. TRAF6 and TAK1 are downstream signals of TGF-β1 and belong to noncanonical signaling. Activation of the TGF-β1/ TRAF6/TAK1 signaling pathway can upregulate connective tissue growth factor (CTGF) expression and contribute to the proliferation of atrial fibroblasts [5]
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