Cytokine therapy prevents left ventricular remodeling and dysfunction after myocardial infarction through neovascularization

Abstract

Pretreatment with a combination of granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) has been reported to attenuate left ventricular (LV) remodeling after acute myocardial infarction (MI). We here examined whether the cytokine treatment started after MI has also beneficial effects. Anterior MI was created in the recipient mice whose bone marrow had been replaced with that of transgenic mice expressing enhanced green fluorescent protein (GFP). We categorized mice into five groups according to the following treatment: 1) saline; 2) administration of G-CSF and SCF from 5 days before MI through 3 days after; 3) administration of G-CSF and SCF for 5 days after MI; 4) administration of G-CSF alone for 5 days after MI; 5) administration of SCF alone for 5 days after MI. All the three treatment groups with G-CSF showed less LV remodeling and improved cardiac function and survival rate after MI. The number of capillaries, which express GFP, was increased and the number of apoptotic cells was decreased in the border area of all the treatment groups with G-CSF. Even if the cytokine treatment is started after MI, it could prevent LV remodeling and dysfunction after MI--at least in part--through an increase in neovascularization and a decrease in apoptosis in the border area.

Granulocyte colony-stimulating factor improves left ventricular function of doxorubicin-induced cardiomyopathy

“…We determined the dose of G-CSF (100 mg/kg) based on previous studies reporting cardioprotective effects of G-CSF. 13,14 Although this dosage is extremely higher than the clinical dosage to humans (lower than 10 mg/day), it is generally believed that mice have a low sensitivity to human G-CSF as presumed by the unexpectedly poor increase in granulocytes. Untreated control groups were given the same volume of saline.…”

“…9,10 Recent studies have confirmed the effectiveness of G-CSF on ischemic heart diseases and revealed new mechanisms for the effect other than tissue regeneration, that is, acceleration of healing and direct tissue protection. [11][12][13][14][15] On the other hand, there has been only one study reporting benefits of G-CSF on nonischemic cardiomyopathy, 8 and thus little is known on the mechanisms for G-CSF to exert such effects. It would be much worthy to confirm the beneficial effects of G-CSF on DOX-induced cardiomyopathy in particular because of the clinical reason; G-CSF is already accepted for clinical use in combination with DOX to DOXinduced myelosuppression.…”

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

“…Although few animals were treated, this was the first work to show the inefficacy of G-CSF treatment. However, in 2004, two important reports strengthened Orlic's findings in rats [8] and rabbits [9]. Ohtshuca et al showed that post-MI treatment with G-CSF alone (without addition of SCF) in non-splenectomized mice had the same effects as Orlic's original protocol [8].…”

“…However, in 2004, two important reports strengthened Orlic's findings in rats [8] and rabbits [9]. Ohtshuca et al showed that post-MI treatment with G-CSF alone (without addition of SCF) in non-splenectomized mice had the same effects as Orlic's original protocol [8]. On the other hand, Deten and co-workers using exactly the same protocol and the same species (mice) as Orlic found no functional benefits [10].…”

“…These authors reported that even though c-kit + increased from 0.05 to 2.8% in peripheral blood, growth factor treated mice did not improve their cardiac function performance, or decreased MI size or any sign of cardiac regeneration as well as cell therapy. Until that time, the mechanism of G-CSF action was discussed exclusively by increasing cell mobilization and homing to ischemic heart with conflicting results [6,8,[10][11][12][13].…”