Objectives: 

Hepatocyte growth factor (HGF) in addition to its angiogenic, antiapoptotic and antifibrotic effects also acts as potent mitogenic, motogenic and differentiation factor on cardiac and mesenchymal stem cells. We investigated HGF and multidrug resistance protein-1 MDR1 (a cardiac stem cell marker) expression during the development of isoproterenol-induced heart failure in rat left ventricles.

Materials: 

Adult male Wistar rats (n=7 per group) were administered isoproterenol (ISO) i.p. (5 mg/kg/d) and sacrificed after 1, 2, 4, 8 days of treatment. Gene expression was analyzed by real-time PCR using gene-specific primers for HGF, HGF receptor (c-met), hepatocyte growth factor activator inhibitor-1 and -2 (HAI-1, HAI-2), MDR-1 and skeletal alpha-actin (ACTA1) as a marker of cardiac hypertrophy. Results were analyzed by ANOVA.

Results: 

30 % mortality was observed within first 4 days, no rats died later. Left ventricular mass and ACTA1 were increased from day 1 onward (P<0.05). HGF expression increased after 2 days of treatment and remained elevated until day 8 (P<0.05). c-met expression increased after 4 days (P<0.05). HAI-1 mRNA levels were elevated on day 1 and day 2 (P<0.05), then they returned to control levels. Expression of HAI-2 mRNA remained unchanged during the experiment. Expression of MDR1 began to rise on day 2, peaked on day 4 and remained at this level until day 8 (P<0.05).

Conclusions: 

Chronic ISO administration in the rat is able to induce HGF production, however, elevated levels of HAI-1 during first 2 days may prevent HGF activation. The HGF pathway could become fully functional after 4 days of ISO administration, when c-met is upregulated. This coincides with upregulation of MDR1 as marker of one subpopulation of cardiac stem cells. This could, together with antiapoptotic and angiogenic properties of HGF, contribute to initiation of cardiac repair mediated by cardiac resident stem cells.

Grant support: VEGA 1/0981/12