运动性心肌肥厚预适应的抗肥厚记忆及其与交感神经活性的关系

Contribution of sympathetic activation to antihypertrophic memory after regression of exercise-induced physiological myocardial hypertrophy in mice

目的揭示运动引起的生理性心肌肥厚(PMH)消退后是否有抵抗病理性心肌肥厚的记忆及其产生机制。方法建立小鼠运动肥厚预适应与主动脉缩窄(TAC)模型,按随机数字表法分为静息假手术组(Sed+Sham),静息TAC组(Sed+TAC),运动预适应假手术组(Exe+Sham),运动预适应TAC组(Exe+TAC),比索洛尔+运动预适应假手术组(biso+Exe+Sham),比索洛尔+运动预适应TAC组(biso+Exe+TAC),共6个组,12只/组。运动预适应组小鼠进行为期3周的游泳训练,而后检查PMH的产生与消退。测量小鼠体质量、心重、肺重和胫骨长度等数据,用实时荧光定量PCR检测心肌肥厚标志基因肌球蛋白重链7(Mhy7)的表达,用小动物心脏超声与左心导管检测小鼠心功能。最后,用组织学染色分析心肌细胞横截面积大小与心肌纤维化程度。结果与静息组相比,游泳运动3周后小鼠心重体质量比(HW/BW)、心重胫骨长度比(HW/TL)以及心肌细胞横截面积明显增加(P<0.05),而心肌纤维化与Mhy7无明显变化。比索洛尔处理的运动小鼠与静息组小鼠相比HW/BW和HW/TL未见明显差异。游泳运动终止1周后,心肌肥厚指标(HW/BW、HW/TL)消退至基线水平。TAC 4周后,与Sed+TAC组小鼠相比,Exe+TAC组小鼠的左室后壁厚度、HW/BW、HW/TL、肺重体质量比值、左室舒张末压和左室松弛时间常数、心肌细胞横截面积以及纤维化程度明显降低(P<0.05);而左室射血分数和左室最大压力变化速率明显增高(P<0.05)。这些指标在biso+Exe+TAC组与Sed+TAC组小鼠之间无明显差异。结论运动引起的生理性心肌肥厚消退后存有抗病理性肥厚记忆,该记忆的产生可归因于运动引起的交感活性增强。

Objective To investigate whether anti-hypertrophic memory exists after regression of exercise-induced physiological myocardial hypertrophy(PMH)and explore the contribution of sympathetic activation to hypertrophic memory formation.Methods Seventy-two mice were randomized equally into 6 groups,including sedentary sham-operated group,exercise hypertrophic preconditioning(EHP)+sham operation group,bisoprolol(an adrenergicβ1 receptor blocker)+EHP+sham operation group(biso+Exe+Sham group),sedentary group with transverse aortic constriction(TAC)(Sed+TAC group),EHP+TAC group(Exe+TAC group),and bisoprolol+EHP+TAC group(biso+Exe+TAC group).The mice in the EHP groups were subjected to 3 weeks of swimming training,and in the bisoprolol groups,bisoprolol was administered by gavage once daily from two days before till the end of the training.One week after the training,TAC or sham surgery was performed.Echocardiography and hemodynamic measurements were performed to evaluate cardiac function of the mice,and the myocardial tissues were examined histologically to detect cardiac remodeling.Results Compared with the sedentary group,the mice receiving 3 weeks of swimming training had significantly increased heart weight to body weight ratio(HW/BW),HW to tibia length ratio(HW/TL),and the cross-sectional area of the cardiomyocytes(P<0.05).One week after the training,exercise-induced PMH rapidly diminished and both HW/BW and HW/TL recovered the baseline levels.Treatment with bisoprolol obviously prevented the occurrence of PMH.Four weeks after TAC,the left ventricular posterior wall thickness,HW/BW,HW/TL,left ventricular end diastolic pressure and cross-sectional area of cardiomyocytes were all significantly lower(P<0.05)while the left ejection fraction and maximal change rate of left ventricular pressure were significantly higher(P<0.05)in Exe+TAC group than in Sed+TAC group.No significant difference was found in these parameters between biso+Exe+TAC group and Sed+TAC group.Conclusion Anti-hypertrophic memory exists even after the regression of exercise-induced PMH,which may be attributed to the activation of sympathetic nervous system during exercise.