Abstract-The purpose of this study was to investigate the effect of hepatocyte growth factor (HGF) on the pathogenesis of cardiac fibrosis induced by pressure overload in mice. Although cardiac fibrosis is attributed to excess pathological deposition of extracellular matrix components, the mechanism remains unclear. Recent reports revealed that ␣-smooth muscle actin-expressing myofibroblasts are primarily responsible for fibrosis. It is believed that myofibroblasts are differentiated from resident fibroblasts, whereas the transformation of vascular endothelial cells into myofibroblasts, known as endothelial-mesenchymal transition, has been suggested to be intimately associated with perivascular fibrosis. Thus, we hypothesized that HGF prevents cardiac fibrosis by blocking these pathways. We analyzed the pressureoverloaded HGF-transgenic mouse model made by transverse aortic constriction. Human coronary artery endothelial cells and human cardiac fibroblasts were examined in vitro after being treated with transforming growth factor-␤1 or angiotensin II with or without HGF. The amount of cardiac fibrosis significantly decreased in pressure-overloaded HGF-transgenic mice compared with pressure-overloaded nontransgenic controls, particularly in the perivascular region. This was accompanied by a reduction in the expression levels of fibrosis-related genes and by significant preservation of echocardiographic measurements of cardiac function in the HGF-transgenic mice (PϽ0.05). The survival rate 2 months after transverse aortic constriction was higher by 45% (PϽ0.05). HGF inhibited the differentiation of human coronary artery endothelial cells into myofibroblasts induced by transforming growth factor-␤1 and the phenotypic conversion of human cardiac fibroblasts into myofibroblasts. We conclude that HGF reduced cardiac fibrosis by inhibiting endothelialmesenchymal transition and the transformation of fibroblasts into myofibroblasts. 1 The number of cardiovascular deaths has been reduced, but in spite of a marked development in recent devices and medicines, cardiovascular disease still impacts the mortality rate in almost all nations.2 Cardiac fibrosis is often present in end-stage heart failure and is caused by various factors, such as ischemia, 3 pressure overload, 4 and cardiomyopathy, 5 so antifibrotic therapy is believed to be beneficial in preventing heart failure. Although fibrosis, which is attributed to an excess deposition of extracellular matrix (ECM) components, is one of the most common pathological changes found in various organs, including the heart, the detailed mechanism remains unclear. It is worth noting that myofibroblasts are characterized by ␣-smooth muscle actin (␣-SMA) expression and appear to play a major role in the pathogenesis of fibrosis by secreting numerous cytokines, growth factors, and ECM proteins. 6 Myofibroblasts were originally thought to be differentiated from resident fibroblasts activated by acute or chronic stimuli, such as myocardial infarction and pressure overload. On the other ...

Abstract-Our previous study demonstrated that periostin, an extracellular matrix protein, plays an important role in left ventricular remodeling through the inhibition of cell-cell interactions. Because the gene regulation of periostin has not yet been examined, we focused on the effects of angiotensin (Ang) II and mechanical stretch, because Ang II and mechanical stretch are related to cardiac remodeling after myocardial infarction. First, we examined the effects of Ang II on periostin in myocytes and fibroblasts in vitro. Ang II significantly increased periostin through phosphatidylinositol 3-kinase, c-Jun N-terminal kinase, p38, and extracellular signal-regulated kinase 1/2 pathways in myocytes and fibroblasts (PϽ0.05). On the other hand, mechanical stretch also significantly increased periostin expression (PϽ0.05). This increase was inhibited partially, but significantly, by an Ang II receptor blocker, valsartan, and inhibited almost completely by valsartan with the neutralization antibodies for transforming growth factor-␤ and platelet-derived growth factor-BB (PϽ0.05). Therefore, we further examined periostin expression in vivo. Periostin expression was significantly increased in infarcted myocardium (PϽ0.05), and treatment with valsartan significantly attenuated it at 4 weeks after myocardial infarction (PϽ0.05), accompanied by a significant improvement in cardiac dysfunction (PϽ0.05). Overall, the present study demonstrated that Ang II, as well as mechanical stretch, stimulated periostin expression in both cardiac myocytes and fibroblasts, whereas valsartan significantly attenuated the increase in periostin expression. The inhibition of periostin by valsartan might especially contribute to its beneficial effects on cardiac remodeling after myocardial infarction. Key Words: angiotensin II type 1 receptor blockers Ⅲ myocardial infarction Ⅲ adhesions Ⅲ fibrosis Ⅲ ventricular remodeling C ardiac remodeling after myocardial infarction (MI) results in ventricular dysfunction, which contributes to a poor outcome and high mortality. 1 The use of angiotensin (Ang)-converting enzyme inhibitors in patients with MI has improved survival and reduced the rates of major cardiovascular events, 2 and Ang II receptor blockers (ARBs) were expected to prevent cardiac remodeling, like Ang-converting enzyme inhibitors. The Valsartan in Acute Myocardial Infarction Trial demonstrated that an ARB, valsartan, was as effective as a proven regimen of an Ang-converting enzyme inhibitor captopril in improving survival and reducing cardiovascular mortality in patients who suffered an MI. 3,4 Treatment with captopril or valsartan resulted in similar changes in cardiac volume and ejection fraction after MI, 3 whereas treatment with captopril after MI significantly reduced left ventricular (LV) enlargement. 2 On the other hand, periostin is a novel secreted and putative soluble extracellular matrix protein 5 and is known to be expressed in bone and to a lesser extent in lung, kidney, and heart valves but is not found in normal blood vess...

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Although both hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) are potent angiogenic growth factors in animal models of ischemia, their characteristics are not the same in animal experiments and clinical trials. To elucidate the discrepancy between HGF and VEGF, we compared the effects of HGF and VEGF on endothelial progenitor cells under angiotensin II stimulation, which is a well-known risk factor for atherosclerosis. Here, we demonstrated that HGF, but not VEGF, attenuated angiotensin II-induced senescence of endothelial progenitor cells through a reduction of oxidative stress by inhibition of the phosphatidylinositol-3,4,5-triphosphate/rac1 pathway. Potent induction of neovascularization of endothelial progenitor cells by HGF, but not VEGF, under angiotensin II was also confirmed by in vivo experiments using several models, including HGF transgenic mice.