Novel mechanism of cardiac protection by valsartan: synergetic roles of TGF-β1 and HIF-1α in Ang II-mediated fibrosis after myocardial infarction.

Abstract

Transforming growth factor (TGF)-β1 is a known factor in angiotensin II (Ang II)-mediated cardiac fibrosis after myocardial infarction (MI). Hypoxia inducible factor-1 (Hif-1α) was recently demonstrated to involve in the tissue fibrosis and influenced by Ang II. However, whether Hif-1α contributed to the Ang II-mediated cardiac fibrosis after MI, and whether interaction or synergetic roles between Hif-1α and TGF-β pathways existed in the process was unclear. In vitro, cardiac cells were incubated under hypoxia or Ang II to mimic ischaemia. In vivo, valsartan was intravenously injected into Sprague-Dawley rats with MI daily for 1 week; saline and hydralazine (another anti-hypertensive agent like valsartan) was used as control. The fibrosis-related proteins were detected by Western blotting. Cardiac structure and function were assessed with multimodality methods. We demonstrated in vitro that hypoxia would induce the up-regulation of Ang II, TGF-β/Smad and Hif-1α, which further induced collagen accumulation. By blocking with valsartan, a blocker of Ang II type I (AT1) receptor, we confirmed that the up-regulation of TGF-β/Smad and Hif-1α was through the Ang II-mediated pathway. By administering TGF-β or dimethyloxalylglycine, we determined that both TGF-β/Smad and Hif-1α contributed to Ang II-mediated collagen accumulation and a synergetic effect between them was observed. Consistent with in vitro results, valsartan significantly attenuated the expression of TGF-β/Smad, Hif-1α and fibrosis-related protein in rats after MI. Heart function, infarcted size, wall thickness as well as myocardial vascularization of ischaemic hearts were also significantly improved by valsartan compared with saline and hydralazine. Our study may provide novel insights into the mechanisms of Ang II-induced cardiac fibrosis as well as into the cardiac protection of valsartan.

• Authors: Xizhong Sui, Hongchao Wei, Dacheng Wang
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 19 Issue 8 Pg. 1773-82 (Aug 2015) ISSN: 1582-4934 [Electronic] England
• PMID: 25823960 (Publication Type: Journal Article)
• Copyright: © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Chemical References

• Cardiotonic Agents
• Hypoxia-Inducible Factor 1, alpha Subunit
• Transforming Growth Factor beta1
• Angiotensin II
• Valsartan
• Collagen
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9

Topics

• Angiotensin II
• Animals
• Blood Vessels (drug effects, pathology, physiopathology)
• Cardiotonic Agents (pharmacology, therapeutic use)
• Collagen (metabolism)
• Fibrosis
• Heart Function Tests (drug effects)
• Hemodynamics (drug effects)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Male
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Myocardial Infarction (diagnostic imaging, drug therapy, pathology, physiopathology)
• Rats, Sprague-Dawley
• Transforming Growth Factor beta1 (metabolism)
• Ultrasonography
• Valsartan (pharmacology, therapeutic use)