Role for Granulocyte Colony Stimulating Factor in Angiotensin II-Induced Neutrophil Recruitment and Cardiac Fibrosis in Mice

BACKGROUND Granulocyte colony stimulating factor (G-CSF) is a key mediator of neutrophil infiltration and is profibrotic in the liver, lung, and infarcted heart, but its roles in angiotensin II (Ang II)-induced hypertension and cardiac remodeling have not been fully determined. Thus, we sought to investigate the causal relation of G-CSF to neutrophil recruitment and cardiac fibrosis in C57BL/6J mice. METHODS Hypertension and cardiac fibrosis were induced in wild-type (WT) mice receiving continuous infusion of Ang II (1,500 ng/kg/min). After 7 days, heart sections were stained with hematoxylin and eosin, Masson's trichrome, and immunohistochemistry. The mRNA expression of cytokines was detected by real-time polymerase chain reaction analysis. The protein levels were measured by Western blot analysis. RESULTS After Ang II infusion, myocardial G-CSF expression was significantly elevated in the hearts. Moreover, WT mice exhibited increased blood pressure, marked neutrophil accumulation, proinflammatory cytokine expression, reactive oxygen species production, and cardiac fibrosis after 7 days of Ang II infusion. However, administration of anti-G-CSF neutralizing antibody, but not with control immunoglobulin G, significantly attenuated these effects. In addition, neutralizing G-CSF antibody reversed Ang II-induced activation of ERK1/2, STAT3, and AKT signaling pathways in the hearts. CONCLUSIONS This study demonstrates that G-CSF plays a critical role in hypertension and cardiac fibrosis and targeting this cytokine may be a novel therapeutic strategy to ameliorate hypertensive heart disease.