Isoproterenol modulates cardiac hepatocyte growth factor expression in the rat heart

P Krenek, L Pivackova, H Cernecka, P Ochodnicky, B Gajdacova, A Adameova, J Kyselovic, J Klimas. Comenius University, Faculty of Pharmacy, Department of Pharmacology and Toxicology, 83232, Slovakia

Objectives. Hepatocyte growth factor (HGF) is a factor with antiapoptotic properties, it stimulates endothelial cell proliferation, angiogenesis and tissue regeneration, has antifibrotic actions and may play a cardioprotective role in myocardial post infarction remodeling. We investigated the time-course of HGF expression during the development of isoproterenol-induced heart failure in the rat. Methods. Adult male Wistar rats were given isoproterenol intraperitoneally (5 mg/kg, n=7 per group). Rats were sacrificed 0.5, 1, 2, 4, 8, 24 h after isoproterenol administration, or 2, 4, 8 days of daily isoproterenol injections. Total RNA was isolated from left ventricles, reverse-transcribed and analyzed by real-time PCR analysis using gene-specific primers for hepatocyte growth factor (HGF), HGF receptor (c-met), hepatocyte growth factor activator inhibitor-1 (HAI-1). Atrial natriuretic peptide (ANP) was used as a marker of cardiac hypertrophy. Results were analyzed using one way ANOVA and are expressed as mean±standard error of the mean. Results. Isoproterenol administration was associated with about 20 % mortality within 3 days of treatment and a decline in left ventricular function maximal by day 8 (101±5 mmHg vs 122±2 mmHg, P<0.05). Relative left ventricular weight and expression of cardiac hypertrophy marker ANP increased 15±3.0 fold within 24 hours and remained elevated for 8 days (P<0.05). In the left ventricle, HGF expression increased 2.4±0.2 fold after 2 days of isoproterenol treatment and remained elevated until day 8 (P<0.05). c-met expression transiently, but highly variably increased within 4 hours (24±13 fold, P=NS), returned to control levels within 24 h and increased again after 4 days (380±170 fold, P<0.05). HAI-1 mRNA levels were elevated more than twofold on day 1 and day 2 (P<0.05), then they returned to control levels. Conclusions. Chronic beta adrenergic stimulation in the rat leads to a late upregulation of HGF that is preceded by a transient upregulation of HAI-1 which could limit HGF production within the heart. The HGF pathway could become fully functional after 4 days of isoproterenol administration, when c-met is upregulated in parallel with HGF. HGF overexpression could play a protective role in isoproterenol-induced heart failure

The project was supported by: VEGA 1/0981/12.