Cardioprotective effects of granulocyte colony-stimulating factor in angiotensin II-induced cardiac remodelling.
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.
Jia
Nan
N
Department of Cardiology, Shanghai Jiaotong University Affiliated First People's Hospital, China. jiananchina@hotmail.com
Dong
Peixin
P
Huang
Qiuping
Q
Jin
Wei
W
Zhang
Jianjun
J
Dai
Qiuyan
Q
Liu
Shaowen
S
D000804:Angiotensin II / Q000008:administration & dosage; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D005355:Fibrosis; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D015918:Infusion Pumps, Implantable; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D053495:Osteopontin / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*
D012333:RNA, Messenger; D011994:Recombinant Proteins; C506896:Spp1 protein, mouse; D053495:Osteopontin; D000804:Angiotensin II; D016179:Granulocyte Colony-Stimulating Factor; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2