The Antiapoptotic Effect of Granulocyte Colony-stimulating Factor Reduces Infarct Size and Prevents Heart Failure Development in Rats

Abstract

Background/Aim. Granulocyte colony-stimulating factor (G-CSF) reduces myocardial injury and improves cardiac function after myocardial infarction (MI). We investigated the early alterations provided by G-CSF and the chronic repercussions in infarcted rats. Methods. Male Wistar rats (200-250g) received vehicle (MI) or G-CSF (MI-GCSF) (50 µg/kg, sc) at 7, 3 and 1 days before MI surgery. Afterwards MI was produced and infarct size was measured 1 and 15 days after surgery. Expression of anti- and proapoptotic proteins was evaluated immediately before surgery. 24 hours after surgery, apoptotic nuclei were evaluated. Two weeks after MI, left ventricular (LV) function was evaluated, followed by in situ LV diastolic pressure-volume evaluation. Results. Infarct size was decreased by 1 day pre-treatment before occlusion (36±2.8 vs. 44±2.1% in MI; P<0.05) and remained reduced at 15 days after infarction (28±2.2 vs. 36±1.4% in MI; P<0.05). G-CSF pretreatment increased Bcl-2 and Bcl-xL protein expression, but did not alter Bax in LV. Apoptotic nuclei were reduced by treatment (Sham: 0.46±0.42, MI: 15.5±2.43, MI-GCSF: 5.34±3.34%; P<0.05). Fifteen days after MI, cardiac function remained preserved in G-CSF pretreated rats. The LV dilation was reduced in MI-G-CSF group as compared to MI rats, being closely associated with infarct size. Conclusion. The early beneficial effects of G-CSF were essentials to preserve cardiac function at a chronic stage of myocardial infarction.

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“…However, a different regulation pattern is noticed during the development of heart failure. The GCSF reduces myocardial injury and improves cardiac function in rats with acute and chronic myocardial infarction [31,32] and is regarded as a potential cardiac repair therapy for subjects with myocardial infarction [30]. The GMCSF is able to enhance collateral blood flow of patients with chronic myocardial infarction [33]; however, plasma levels of GMCSF in patients with heart failure are highly associated with LV dysfunction [34].…”

Erythrocytic Mobilization Enhanced by the Granulocyte Colony-Stimulating Factor Is Associated with Reduced Anthrax-Lethal-Toxin-Induced Mortality in Mice

“…G-CSF is also used to prevent or shorten neutropenia in chemotherapy-induced or primary congenital neutropenia [42], and mobilize hematopoietic stem cells to peripheral blood for transplantation [43]. Probably because of the anti-apoptotic and anti-inflammatory effects, G-CSF has also been used to treat nonhematopoietic targets including cerebral ischemia [44], spinal cord ischemia [45], infarct heart [46], and end stage liver disease [47]. Consequently, the effects of G-CSF on other cell types (e.g., macrophage, lymphocyte, endothelial, dendritic cells, cardiomyocytes, and smooth muscle) may not be completely excluded from the rescue mechanism of G-CSF.…”

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“…G-CSF also induced antiapoptotic proteins and inhibited apoptotic death of cardiomyocytes [14]. Baldo MP et al recently reported that G-CSF preserved left ventricular function through early infarct size reduction and the attenuation of cardiac remodeling after MI via anti-apoptotic protein upregulation and an early reduction in cardiomyocyte apoptosis [15]. Minatoguchi et al hypothesized that G-CSF accelerate the healing of MI wounds and they reported that it accelerated absorption of necrotic tissues by increasing macrophage numbers, and reduced granulation and scar tissue by promoting the expression of matrix metalloproteinases [16].…”