Abstract: BACKGROUND: Exercise training is an important non-drug rehabilitation method for many heart diseases, and it can also enhance the heart’s tolerance to adverse stressors (such as myocardial ischemia), that is, exercise preconditioning. Granulocyte colony-stimulating factor can effectively mobilize stem cell homing and differentiation and promote the repair of damaged myocardium. However, the effect of the combination of the two treatments is not yet clear.
OBJECTIVE: To explore the effect of granulocyte colony-stimulating factor supplementation combined with high-intensity intermittent exercise preconditioning on cardiac remodeling in rats with acute myocardial infarction and investigate its possible mechanism.
METHODS: Totally 58 male Wistar rats were divided into sham group (n=10), model group (n=12), model drug group (n=12), model exercise group (n=12) and model combined treatment group (n=12). The myocardial infarction rat model was made by coronary artery ligation. The model exercise group and the model combined treatment group were pretreated with 8 weeks of high-intensity intermittent exercise on an electric treadmill before modeling. The model drug group and the model combined treatment group were subcutaneously injected with human recombinant granulocyte colony-stimulating factor 3 hours after modeling for 5 days (10 μg/kg per day). At 8 weeks after administration, echocardiography was used to detect heart structure and function; heart was stained with 2,3,5-triphenyltetrazolium chloride and Masson staining to obtain myocardial infarct area and collagen volume fraction, respectively. Vessel density and cell apoptosis rate were detected by immunofluorescence. Real-time fluorescent quantitative PCR was utilized to detect the mRNA expression of embryonic genes (brain natriuretic peptide, β-myosin heavy chain) and myocardial contraction regulatory factors (α-myosin heavy chain, sarcoplasmic reticulum Ca2+-ATPase). Western blot assay was used to detect the protein expression of cardiac stromal cell-derived factor 1, CXC chemokine receptor protein 4, Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), Bcl2, Bax, and cleaved caspase-3.
RESULTS AND CONCLUSION: (1) Compared with sham group, myocardial infarct size, collagen volume fraction, and apoptosis rate increased (P < 0.05); vessel density, left ventricular fractional shortening, and left ventricular ejection fraction decreased (P < 0.05); brain natriuretic peptide and β-myosin heavy chain mRNA increased (P < 0.05), α-myosin heavy chain and sarcoplasmic reticulum Ca2+-ATPase mRNA and α-myosin heavy chain/β-myosin heavy chain ratio decreased (P < 0.05); stromal cell-derived factor 1, CXC chemokine receptor protein 4, Bax, cleaved caspase-3 protein expression increased (P < 0.05); p-JAK2, p-STAT3, and Bcl-2 protein expression decreased (P < 0.05) in the model group. (2) Compared with the model group, the above indexes in the model drug and model exercise groups were significantly improved (P < 0.05). Compared with the model drug and model exercise groups, the above parameters were further ameliorated (P < 0.05) in the model combined treatment group. (3) The results showed that supplementation of granulocyte colony-stimulating factor or high-intensity intermittent exercise preconditioning alone can improve cardiac remodeling in rats with acute myocardial infarction, and the combined therapy has a better effect, which may be related to the induction of stem cell homing and the activation of JAK2/STAT3 signaling pathway to inhibit cardiomyocyte apoptosis.

Key words: granulocyte colony-stimulating factor, high-intensity intermittent exercise, preconditioning, acute myocardial infarction, cardiac remodeling