关键词: 运动预处理, 心肌梗死, 骨髓间充质干细胞, 心脏重构, 炎症反应, 微环境

Abstract: BACKGROUND: Stem cell therapy has broad prospects in improving cardiac remodeling after myocardial infarction; however, alteration in the myocardial microenvironment affects the therapeutic efficacy of stem cells. Exercise preconditioning is similar to ischemic preconditioning and can have a protective effect on the myocardium. However, little attention has been paid to the effects and mechanisms of the combined effects of exercise preconditioning and stem cell transplantation.
OBJECTIVE: To observe the effect of exercise preconditioning on bone marrow mesenchymal stem cell transplantation in rats with myocardial infarction and to explore the mechanism of local inflammatory microenvironment.
METHODS: Eighty female SD rats were randomly divided into sham operation group, model group, transplantation group, and combination group, with 20 rats in each group. The rat model of myocardial infarction was made by ligating the left anterior descending branch of coronary artery. The sham operation group was only threaded without ligature. The transplantation and combination groups were injected with bone marrow mesenchymal stem cells of male rats into the myocardium after modeling. In addition, the combination group also required 8 weeks of treadmill exercise (i.e., exercise preconditioning) before modeling. Four weeks after stem cell transplantation, exercise performance was measured by incremental exercise exhaustion test; cardiac structure and function were measured by echocardiography; left ventricular hemodynamics was measured by pressure-volume catheterization, and myocardial histopathology was observed by in situ staining and myocardial collagen volume fraction was obtained. Quantitative reverse transcription polymerase chain reaction was used to detect left ventricular pro-inflammatory factor (interleukin-1β, interleukin-6, tumor necrosis factor-α), anti-inflammatory factor (interleukin-10), sex-determining region of Y chromosome, and fetal genes (atrial natriuretic peptide, brain natriuretic peptide, β-myosin heavy chain) mRNA expression level at 1, 7 days and 4 weeks after stem cell transplantation.
RESULTS AND CONCLUSION: (1) Four weeks after stem cell transplantation: compared with sham operation group, exercise performance, and left ventricular ejection fraction were reduced (P < 0.05); myocardial infarction area, cardiomyocyte cross-sectional area, and collagen volume fraction were increased (P < 0.05); the mRNA expression of fetal genes and pro-inflammatory factors were up-regulated (P < 0.05), and the mRNA expression of interleukin-10 was down-regulated (P < 0.05) in the model group. Compared with the model group, exercise performance and left ventricular ejection fraction were increased (P < 0.05); myocardial infarction area, cardiomyocyte cross-sectional area, and collagen volume fraction were decreased (P < 0.05); mRNA expression of fetal genes and pro-inflammatory factors was down-regulated (P < 0.05), and that of interleukin-10 had no significant change (P > 0.05) in the transplantation group. Compared with the transplantation group, all the above indicators in the combination group were further improved (P < 0.05). (2) One day and 7 days after stem cell transplantation, compared with the transplantation group, the mRNA expression of sex-determining region of Y chromosome in the combination group increased (P < 0.05). (3) Correlation analysis showed that interleukin-1β, interleukin-6 (except on the 1st day after transplantation), and tumor necrosis factor-α were negatively correlated with the mRNA expression of sex-determining region of Y chromosome (P < 0.05), while interleukin-10 was positively correlated with that of sex-determining region of Y chromosome (P < 0.05). These findings suggest that exercise preconditioning can enhance the effect of bone marrow mesenchymal stem cell transplantation in rats with myocardial infarction, which is characterized by suppression of cardiac remodeling and further amelioration of cardiac function. The mechanism is related to the improvement of the myocardial inflammatory microenvironment to promote bone marrow mesenchymal stem cell retention and survival.

Key words: exercise preconditioning, myocardial infarction, bone marrow mesenchymal stem cell, cardiac remodeling, inflammatory response, microenvironment