β3肾上腺素能受体上调对慢性心力衰竭大鼠左心室p38 MAPK表达的影响

Effect of β3 adrenergic receptor upregulation on p38 MAPK expression in left ventricular of rats with chronic heart failure

目的:探讨β3肾上腺素能受体(β3-AR)对慢性心力衰竭(CHF)大鼠左心室p38分裂原激活的蛋白激酶(p38 MAPK)表达的影响。方法:18只雄性Wistar大鼠随机选取6只作为假手术组,另12只采用主动脉缩窄法建立CHF动物模型,将存活大鼠再随机分为CHF组(n=5)和BRL组(n=6),BRL组大鼠接受尾静脉注射β3-AR特异性激动剂BRL-37344(0.4 nmol/kg·min,每次持续10 min,每周2次,共4周)。右颈总动脉插管检测大鼠血流动力学指标,HE染色检测大鼠左心室肌病理学变化,RT-PCR检测大鼠左心室β3-AR mRNA表达,蛋白免疫印迹法检测大鼠左心室p-p38 MAPK蛋白表达。结果:与假手术组比较,CHF组和BRL组大鼠左心室收缩末压(LVESP)、左心室内压最大上升速率(+dp/dtmax)和左心室内压最大下降速率(-dp/dtmax)的绝对值均降低(P<0.01),左心室舒张末压(LVEDP)升高(P<0.01);左心室质量指数(LVMI)均增加(P<0.01)。与CHF组比较,BRL组大鼠的LVESP、dp/dtmax降低(P<0.01),LVEDP、LVMI升高(P<0.05),大鼠左心室肌病理学改变更显著(P<0.05)。与假手术组比较,CHF组和BRL组大鼠左心室β3-AR mRNA表达水平均上调(P<0.01),其中BRL组大鼠β3-AR表达水平较CHF组升高(P<0.01)。与假手术组比较,CHF组和BRL组大鼠左心室p-p38MAPK蛋白表达水平均升高(P<0.01),其中BRL组大鼠p-p38MAPK表达水平较CHF组有升高趋势,但差异无统计学意义(P=0.065)。结论:虽然左心室β3-AR表达上调导致CHF大鼠心室重构、功能下降进一步加重,但β3-AR激动可能对p38 MAPK表达无明显影响。

Objective:To investigate the effect ofβ3 adrenergic receptor(β3-AR)on the expression of p38 mitogen-activated protein kinase(p38 MAPK)in left ventricle of chronic heart failure(CHF)rats.Methods:Eighteen male Wistar rats were randomly selected as the sham operation group.Another 12 rats were used for animal modeling of CHF by aortic coarctation,and subsequently,11 surviving rats were randomized into the CHF group(n=5)and BRL group(n=6).The rats in the BRL group received tail vein injection of BRL-37344(specificβ3-AR agonist)at a dose of 0.4 nmol/kg/min given in 10 min,twice a week for 4 weeks.The hemodynamics of the rat were detected by right common carotid artery catheterization.The pathological changes in left ventricular myocardium were detected by HE staining.The expression ofβ3-AR mRNA and p-p38 MAPK protein in the left ventricle of rats was detected by RT-PCR and Western blot,respectively.Results:Compared with the sham operation group,the CHF group and the BRL group showed lower absolute values of left ventricular end-systolic pressure(LVESP),maximum rates of rise(+dp/dtmax)and fall(-dp/dtmax)of the left ventricular pressure(P<0.01),as well as increases in left ventricular end-diastolic pressure(LVEDP)(P<0.01)and left ventricular mass index(LVMI)(P<0.01).Compared with CHF group,the BRL group showed lower LVESP and dp/dtmax(P<0.01),increased LVEDP and LVMI(P<0.05),and the more significant changes in pathology of left ventricular myocardium(P<0.05).Compared with the sham operation group,the expression ofβ3-AR mRNA in the left ventricle of CHF group and BRL group was up-regulated(P<0.01).The expression level ofβ3-AR was higher in BRL group than that that in CHF group(P<0.01).Compared with the sham operation group,the expression of p-p38 MAPK protein in the left ventricle of CHF group and BRL group was increased(P<0.01).The expression level of p-p38 MAPK in BRL group was higher than that in CHF group,but the difference did not reach the level of statistical significance(P=0.065).Conclusion:Although the up-regulation of left ventricularβ3-AR leads to a further aggravation of ventricular remodeling and dysfunction in CHF rats,activation ofβ3-AR may not exhibit any significant effect on p38 MAPK expression.