CARDIOPROTECTIVE EFFECTS OF GRANULOCYTE COLONY‐STIMULATING FACTOR IN ANGIOTENSIN II‐INDUCED CARDIAC REMODELLING

Abstract

1. Granulocyte colony stimulating factor (G-CSF) is reported to have a beneficial effect on cardiac dysfunction in postinfarction and doxorubicin-induced cardiomyopathy. Thus, the aim of the present study was to investigate the effects of G-CSF on cardiac remodelling in angiotensin (Ang) II-induced hypertrophy. 2. Four groups of mice were investigated. The first group served as a control group. The second group was injected with recombinant human G-CSF (10 microg/kg per day, s.c.) on the first 5 days of each week and treatment was continued for 4 weeks. An osmotic minipump was implanted subcutaneously into each mouse in the third group so that pressor doses of AngII (2.88 mg/kg per day) or saline could be administered over a period of 4 weeks. The fourth group was infused with AngII (2.88 mg/kg per day) and injected with G-CSF (10 microg/kg per day, s.c.) for 4 weeks. 3. Angiotensin II treatment significantly elevated blood pressure and caused cardiac hypertrophy and fibrosis in mice. Treatment of mice with G-CSF did not reduce the AngII-induced increase in blood pressure, but ameliorated the development of cardiac fibrosis and hypertrophy. Infusion of AngII induced upregulation of angiotensin-converting enzyme (ACE) expression and downregulation of ACE2 expression. Treatment with G-CSF reduced cardiac levels of ACE and increased ACE2 expression. In addition, G-CSF treatment reduced the expression of osteopontin (OPN) and phospho-p70S6 kinase, which were upregulated by AngII infusion. 4. These results suggest that G-CSF reduces AngII-induced hypertrophy. Modulation of the expression of the ACE isoforms contributes to regression of AngII-induced cardiac hypertrophy. The effect of G-CSF to prevent cardiac fibrosis and hypertrophy may be mediated, in part, via inhibition of OPN expression and p70S6 kinase phosphorylation.