Original Article Hepatocyte growth factor prevents ventricular remodeling and dysfunction in mice via Akt pathway and angiogenesis Yigang Wang a , Nauman Ahmad a , Maqsood A. Wani b , Muhammad Ashraf a, * a Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, College of Medicine, 231Albert Sabin Way, Cincinnati, OH 45267-0529, USA b Research Foundation, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229-3039, USA Received 2 June 2004; received in revised form 22 July 2004; accepted 14 September 2004 Abstract This study determines the effect of hepatocyte growth factor (HGF) on post-infarction left ventricular (LV) remodeling and cardiac function. In mice, on day 1 after myocardial infarction (MI), HGF (0.45 mg/kg per day) was injected into the tail vein for 7 days (n = 12). In the control mice (n = 12), 0.9% sodium chloride was injected instead of HGF. Hemodynamic data were obtained in vehicle treated control and HGF-treated hearts 4 weeks after the onset of MI. In the HGF-treated group, cardiac function was well preserved as indicated by LV pressure–volume relationship. These mice exhibited better LV systolic and diastolic function. The infarcted LV wall in HGF-treated heart was thicker as compared to vehicle treated group. Fibrosis and infarct size of the ventricular wall was significantly reduced in the HGF-treated hearts. 5-Bromo-2′-deoxy-uridine (BrdU) and Ki67 positive cardiomyocytes were observed in the border area of the HGF-treated infarcted hearts. c-Met and c-kit positive cardiomyocytes were observed in the border area and epicardium. Angiogenesis was significantly enhanced in HGF-treated hearts as determined by vessel density per unit area. A significant reduction in apoptosis in the HGF-treated hearts was observed compared with control hearts, and was strongly associated with increased Akt activation. Treatment with HGF improved heart function through angiogenesis, ventricular wall thickening, and hypertrophy of cardiomyocytes. The antiapoptotic effect of HGF was mediated by activation of PI3-kinase/Akt pathway. © 2004 Elsevier Ltd. All rights reserved. Keywords: Heart remodeling; Hepatocyte growth factor; Myocardial infarction; Angiogenesis; Apoptosis 1. Introduction Hepatocyte growth factor (HGF) is a disulfide het- erodimeric protein originally characterized as a potent mito- gen for mature hepatocytes [1,2]. HGF is known to induce angiogenesis, morphogenesis and prevents apoptosis [3,4]. HGF plays a role as a strong promoter for regeneration and protection of many organs [5,6]. Recently, it was reported that HGF transfection into the myocardium, attenuated ischemia/reperfusion injury [7]. HGF protected against ischemia/reperfusion injury and enhanced survival of the myocardium after acute myocardial infarction (MI) [1,8]. Because MI causes left ventricular (LV) dilatation, dimin- ishes cardiac performance, and results in poor recovery of function [9]; early treatment with HGF may improve cardiac function after MI. Meanwhile, evidence accumulated from many reports has established a beneficial effect of Akt kinase activation together with potentiation of myocardial stem cells. This protein kinase is activated by insulin and various growth factors and functions in PI3-kinase dependent path- way [10]. Akt is an effector molecule for many cellular functions initiated by growth factors [11] and is involved in regulation of gene transcription, protein synthesis, cell sig- naling, cell hypertrophy and cell survival [12,13]. Recent evidence suggests that Akt promotes cell survival by actively inhibiting apoptosis. However, the effect of Akt activation by HGF on overall apoptosis, infarction, or cardiac function is unknown. It has also been reported that HGF did not induce Akt phosphory- lation [1], and this discrepancy could be due to the different animal model or experimental design used in these studies. * Corresponding author. Tel.: +1-513-558-0145; fax: +1-513-558-0807. E-mail address: muhammad.ashraf@uc.edu (M. Ashraf). Journal of Molecular and Cellular Cardiology 37 (2004) 1041–1052 www.elsevier.com/locate/yjmcc 0022-2828/$ - see front matter © 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.yjmcc.2004.09.004