Abstract: BACKGROUND: Stem cell transplantation is a novel therapy for myocardial infarction, but the extremely hostile microenvironment in the infarct area results in low survival rate of stem cells and little long-term effect. Exercise preconditioning is a way to induce endogenous protective effects through exercise, which can be used as a new strategy for prevention and treatment of cardiac rehabilitation.
OBJECTIVE: To evaluate whether exercise preconditioning potentiates the cardioprotective effects of adipose-derived stem cell transplantation following myocardial infarction in rats and to explore the mechanism of angiogenesis.
METHODS: Six-week-old male SD rats were randomly divided into control group, modeling group, stem cell group, and stem cell plus exercise group. Acute myocardial infarction model was made by coronary artery occlusion, and sham operation was performed in control group. The stem cell plus exercise group underwent aerobic exercise for 8 weeks before modeling, and adipose-derived stem cell transplantation was performed 30 minutes after modeling. The stem cell group performed only adipose-derived stem cell transplantation. One and seven days after stem cell transplantation, the expression levels of myocardial total Akt (t-Akt), phosphorylated Akt (p-Akt), vascular endothelial growth factor (VEGF), total endothelial nitric oxide synthase (t-eNOS), and phosphorylated endothelial nitric oxide synthase (p-eNOS) protein were measured by western blotting, and the ratios of p-Akt/t-Akt and p-eNOS/t-eNOS were calculated. At 4 weeks after stem cell transplantation, the heart structure and function as well as myocardial blood flow were detected by color Doppler ultrasound diagnostic system. Myocardial infarction area was measured by TTC staining. Myocardial interstitial collagen deposition was examined by Masson staining. Myocardial capillary density was detected by immunofluorescence staining, and myocardial apoptosis was measured by TUNEL staining. 
RESULTS AND CONCLUSION: (1) Four weeks after stem cell transplantation: Compared with control group, left ventricular shortening fraction, left ventricular ejection fraction, myocardial capillary density, and myocardial blood flow decreased (P < 0.05), myocardial infarction area, collagen volume fraction, and apoptosis increased (P < 0.05) in the modeling group. Compared with the modeling group, the above indexes (except for left ventricular fractional shortening and left ventricular ejection fraction) in the stem cell group improved (P < 0.05). Compared with the stem cell group, the above parameters were further improved in the stem cell plus exercise group (P < 0.05). (2) One day after stem cell transplantation: Compared with the control group, the protein expression of t-Akt, p-Akt, VEGF, t-eNOS, p-eNOS and the ratio of p-Akt/t-Akt and p-eNOS/t-eNOS had no significant changes in the modeling group (P > 0.05). Compared with the modeling group, there were no significant changes in the above indexes in the stem cell group (P > 0.05), and p-Akt protein expression and the ratio of p-Akt/t-Akt were up-regulated in the stem cell plus exercise group (P < 0.05). (3) Seven days after stem cell transplantation: Compared with the control group, the protein expression of p-Akt, VEGF, p-eNOS and the ratio of p-Akt/t-Akt and p-eNOS/t-eNOS were decreased in the modeling group (P < 0.05). Compared with the modeling group, there were no significant changes in all parameters in the stem cell group (P > 0.05), and the protein expression of p-Akt, VEGF p-eNOS and the ratio of p-Akt/t-Akt and p-eNOS/t-eNOS were increased in the stem cell plus exercise group (P < 0.05). These findings confirm that exercise preconditioning can potentiate the therapeutic effect of adipose-derived stem cells on cardiac remodeling in rats with myocardial infarction, and its mechanism is associated with the promotion of myocardial angiogenesis and blood perfusion.

Key words: stem cell, adipose-derived stem cell, exercise preconditioning, myocardial infarction, angiogenesis, cardiac remodeling, blood perfusion