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-We previously reported that overexpression of full-length periostin, Pn-1, resulted in ventricular dilation with enhanced interstitial collagen deposition in a rat model. However, other reports have documented that the short-form splice variants Pn-2 (lacking exon 17) and Pn-4 (lacking exons 17 and 21) promoted cardiac repair by angiogenesis and prevented cardiac rupture after acute myocardial infarction. The apparently differing findings from those reports prompted us to use a neutralizing antibody to selectively inhibit Pn-1 by blockade of exon 17 in a rat acute myocardial infarction model. Administration of Pn neutralizing antibody resulted in a significant decrease in the infarcted and fibrotic areas of the myocardium, which prevented ventricular wall thinning and dilatation. The inhibition of fibrosis by Pn neutralizing antibody was associated with a significant decrease in gene expression of fibrotic markers, including collagen I, collagen III, and transforming growth factor-β1. Importantly, the number of α-smooth muscle actin-positive myofibroblasts was significantly reduced in the hearts of animals treated with Pn neutralizing antibody, whereas cardiomyocyte proliferation and angiogenesis were comparable in the IgG and neutralizing antibody groups. Moreover, the level of Pn-1 expression was significantly correlated with the severity of myocardial infarction. In addition, Pn-1, but not Pn-2 or Pn-4, inhibited fibroblast and myocyte attachment, which might account for the cell slippage observed during cardiac remodeling. Collectively, these results indicate that therapeutics that specifically inhibit Pn exon-17, via a neutralizing antibody or drug, without suppressing other perisotin variants might offer a new class of medication for the treatment of acute myocardial infarction patients. Correspondence to Ryuichi Morishita, Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, 2-2 Yamada-oka Suita 565-0871, Japan. E-mail morishit@cgt.med.osaka-u.ac.jp or Yoshiaki Taniyama, Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, 2-2 Yamada-oka Suita 565-0871, Japan. E-mail taniyama@cgt.med.osaka-u. Taniyama et al Cardiac Remodeling and Periostin 357showed that left ventricular hypertrophy and remodeling were attenuated in Pn knockout mice after MI, whereas there was no difference in cardiomyocyte content. 13,14 On the contrary, Pn-4 lacking exon 17 and 21 administration protected against cardiac rapture in a Pn knockout mouse line that models AMI, suggesting that Pn-4 plays beneficial roles in pathological conditions, such as MI, 15 whereas Pn-1 promotes the opposite effect during cardiac remodeling. Moreover, Pn-2, which lacks exon 17, induces angiogenesis and myogenesis.16 Therefore, we hypothesized that selective blockade of Pn-1, but not Pn-2 and -4, might offer preferable outcome after acute MI.In this study, neutralizing antibody against Pn exon 17 was used for selective blockade of Pn-1 and tested in a rat MI model. MethodsSee online-o...

The present study demonstrates that the increase in metalloproteinases through FAK-ERK signaling by HGF promotes myofibroblast apoptosis. Activation of metalloproteinases by HGF in the fibrotic kidney might be considered to attenuate the progression of CKD.

Abstract-Angiotensin (Ang) II type 1 receptor blockers have demonstrated beneficial effects beyond blood pressure control in the treatment of chronic kidney disease. There is clinical evidence that telmisartan is more effective than losartan in reducing proteinuria in hypertensive patients with diabetic nephropathy, because it is a partial agonist of peroxisome-proliferator activated receptor-␥ (PPAR␥), as well as an Ang II type 1 receptor blocker (AMADEO Study [A comparison of telMisartan versus losArtan in hypertensive type 2 DiabEtic patients with Overt nephropathy]). In this study, we examined the role of PPAR␥ activation in the renal protective actions of telmisartan using Ang II type 1 receptor-deficient mice. Renal injury was induced in Ang II type 1 receptor-deficient mice by producing unilateral ureteral obstruction, which exhibited severe renal interstitial fibrosis and inflammation. In these mice, telmisartan prevented hydronephrosis induced by unilateral ureteral obstruction more strongly than did losartan. Importantly, the prevention of renal atrophy and fibrosis by telmisartan was significantly attenuated by GW9662, a PPAR␥ antagonist. Interestingly, the downstream effector of PPAR␥ activation by telmisartan is hepatocyte growth factor (HGF), a well-known antifibrotic factor, because renal HGF expression was significantly increased by telmisartan, and a neutralizing antibody against HGF diminished the renal protective action of telmisartan. These beneficial changes by telmisartan were associated with a decrease in the expression of transforming growth factor-␤1 and other proinflammatory and profibrotic cytokine genes through PPAR␥/HGF activation. Our findings provide evidence of organ protective actions of telmisartan through the PPAR␥/HGF pathway, independent of Ang II type 1 receptor blockade. Key Words: hepatocyte growth factor Ⅲ angiotensin receptors Ⅲ angiotensin antagonists Ⅲ PPAR-␣ and -␥ Ⅲ growth factors and cytokines Ⅲ chronic failure (kidney) Ⅲ hypertension (kidney) E xcessive activation of the renin-angiotensin (Ang) system, specifically Ang II, is a key component of the pathogenesis of hypertension, atherosclerosis, coronary artery disease, myocardial infarction, congestive heart failure, and nephropathy. 1 Ang II exerts its effects through 2 different receptors, Ang II type 1 and type 2. The binding of Ang II to the type 1 receptor (AT 1 R) produces vasoconstriction, increases aldosterone release and sympathetic activity, and mediates virtually all of the known adverse cardiovascular effects of Ang II. AT 1 R blockers (ARBs) are selective antagonists of AT 1 R and are widely used to treat hypertension and hypertension-related target organ damage. 2-5 Diabetic nephropathy, the leading cause of end-stage renal disease, is a combination of hemodynamic and metabolic abnormalities that contribute to kidney damage resulting in proteinuria and reduced glomerular filtration rate. 6 Among the available ARBs, telmisartan, one of the second-generation ARBs known as metabosartans, is reported to b...

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