G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes

Abstract

Granulocyte colony-stimulating factor (G-CSF) was reported to induce myocardial regeneration by promoting mobilization of bone marrow stem cells to the injured heart after myocardial infarction, but the precise mechanisms of the beneficial effects of G-CSF are not fully understood. Here we show that G-CSF acts directly on cardiomyocytes and promotes their survival after myocardial infarction. G-CSF receptor was expressed on cardiomyocytes and G-CSF activated the Jak/Stat pathway in cardiomyocytes. The G-CSF treatment did not affect initial infarct size at 3 d but improved cardiac function as early as 1 week after myocardial infarction. Moreover, the beneficial effects of G-CSF on cardiac function were reduced by delayed start of the treatment. G-CSF induced antiapoptotic proteins and inhibited apoptotic death of cardiomyocytes in the infarcted hearts. G-CSF also reduced apoptosis of endothelial cells and increased vascularization in the infarcted hearts, further protecting against ischemic injury. All these effects of G-CSF on infarcted hearts were abolished by overexpression of a dominant-negative mutant Stat3 protein in cardiomyocytes. These results suggest that G-CSF promotes survival of cardiac myocytes and prevents left ventricular remodeling after myocardial infarction through the functional communication between cardiomyocytes and noncardiomyocytes.

Granulocyte–Colony Stimulating Factor Promotes Liver Repair and Induces Oval Cell Migration and Proliferation in Rats

“…28,29 Similarly, G-CSF administration after myocardial infarction in mice induces G-CSFR expression in cardiomyocytes and results in the prevention of cardiac remodeling. 30 Regarding the BMC contribution to liver regeneration, our study shows that the number of BM-derived hepatic cells in G-CSF-treated animals was increased up to 6-fold, as compared with the controls. Peg-G-CSF seemed to be more effective than the nonpegylated molecule, probably owing to an increased serum half-life, even though the difference was not statistically significant (group A vs B, P > .05).…”

The immune system and cardiac repair

“…Growth factors are pleiotropic and multifunctional and induce a diverse range of effects on a variety of cell types involved in infarct healing. In addition to its actions on progenitor cell recruitment, G-CSF may prevent post-infarction remodeling by exerting direct anti-apoptotic effects on cardiomyocytes [358]. Thus, the potential beneficial actions of growth factor therapy in the infarcted myocardium may not be mediated through stem cell mobilization.…”

Granulocyte Colony Stimulating Factor in the Treatment of Cardiac Ischemic Disease. A Decade has Passed: Is it Time to Give Up?

“…Given that and the controversy about the differentiation of HSC into cardiomyocytes [14,15], a number of studies have focused on a possible direct action of G-CSF on cardiomyocytes [9,[16][17][18]. Harada et al [16] demonstrated that cultures of rat and mouse cardiac myocytes and fibroblasts express G-CSF receptor (G-CSFR) and that its expression increased after MI.…”

“…Harada et al [16] demonstrated that cultures of rat and mouse cardiac myocytes and fibroblasts express G-CSF receptor (G-CSFR) and that its expression increased after MI. They further showed that G-CSF therapy prevents LV remodeling and improved cardiac function after MI by activating the Jak-Stat signaling pathway.…”