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.

Specific α7 nicotinic acetylcholine receptor agonist ameliorates isoproterenol‐induced cardiac remodelling in mice through TGF‐β1/Smad3 pathway

“…It is well‐known that the TGF‐β1/Smad3 pathway is a central mediator in cardiac remodelling and exerts multiple biological effects, including cell proliferation, differentiation, apoptosis, autophagy and extracellular matrix production . A large body of evidence has demonstrated that TGF‐β1 is dramatically up‐regulated in the remodelling heart in both patient and animal experimental models, and has been used as a marker of cardiac remodelling .…”

“…It is well‐known that the TGF‐β1/Smad3 pathway is a central mediator in cardiac remodelling and exerts multiple biological effects, including cell proliferation, differentiation, apoptosis, autophagy and extracellular matrix production . A large body of evidence has demonstrated that TGF‐β1 is dramatically up‐regulated in the remodelling heart in both patient and animal experimental models, and has been used as a marker of cardiac remodelling . Moreover, the over‐expression of active TGF‐β1 in the rodent heart induces the fibrotic response, whereas down‐regulation of TGF‐β1 with a neutralizing antibody, antisense oligonucleotides, inhibitors, or genetic deletion of receptors attenuates cardiac remodelling in vivo and in vitro .…”

Hypoxia‐inducible factor 1‐alpha (HIF‐1α) as a factor mediating the relationship between obesity and heart failure with preserved ejection fraction

“…Transfecting hypoxic mouse fibroblasts with HIF‐1α siRNA ameliorates TGF‐β‐induced α‐SMA, a marker of pathologic fibroblast activity, and FGF expression in comparison with fibroblasts transfected with scrambled siRNA . HIF‐1α and TGF‐β play a synergistic role in myocardial fibrosis under hypoxic conditions . HIF‐1α and TGF‐β synergistically increase differentiation of endomyocardial fibroblasts into myofibroblasts that contribute to ECM synthesis .…”

“…Inflammation and resulting fibrosis are integral parts of the pathogenesis of diastolic dysfunction. HIF‐1α plays a synergistic role with angiotensin II in the over expression of matrix metalloproteinases 2 and 9 (MMP 2 and 9) . This is of particular interest considering that MMP 2 and 9 have been intimately implicated in the development of diastolic dysfunction …”

Losartan Attenuates Scar Formation in Filtering Bleb After Trabeculectomy

“…AT1R blockers were shown to suppress TGF-b1 expression in several cell types. 44,45 Sui et al 46 demonstrated that TGF-b/Smad signal pathway contributes to Ang II-mediated collagen accumulation and valsartan, a blocker of AT1R, significantly attenuates the expression of TGF-b/Smad signaling molecules; however, research results are controversial. Another study showed that ARB inhibits collagen synthesis and metabolic imbalance mediated by Ang II, but had no effect on TGF-b1-induced cardiac fibrosis and Smad signaling molecule expression.…”