摘要
目的:观察细胞外信号调节激酶1/2(ERK1/2)在小鼠主动脉弓缩窄压力超负荷诱导的肥厚心肌组织中不同时点的表达变化,探讨肥厚心肌从代偿到失代偿心力衰竭发生中的分子机制。方法:12周龄C57/BL小鼠通过主动脉弓缩窄(TAC)建立心肌肥厚模型,在1、4、8、12、16周时进行高频心脏超声、血流动力学、组织重量及心肌病理学检测,RT-PCR半定量测定心房利钠肽(ANP)、α-肌球蛋白重链(α-MHC)、bcl-2、bax mRNA,Western blotting方法检测磷酸化ERK1/2蛋白表达的变化。同时建立假手术模型,在不同时点给予相同检测后处死。结果:(1)与假手术组比较,缩窄组左室收缩期、舒张期前壁、后壁厚度、左心室收缩末期、舒张末期内径于术后呈逐渐增加趋势;左心室射血分数于术后12周显著降低(P<0.05)。左室收缩压及左室压力上升和下降最大速率于术后4周明显增加,8-12周保持稳定,16周明显下降;左室舒张末压于术后8周持续增加(均P<0.05)。显示心肌由左室肥厚最终发展为心力衰竭。(2)组织形态学天狼猩红染色测量心肌胶原含量及TUNEL染色测定凋亡指数显示从4周到16周呈增加趋势。(3)与假手术组比较,缩窄组心肌组织ANP术后1周至16周表达呈持续性增加;而α-MHC、bcl-2 mRNA表达呈持续性降低;bcl-2/bax比值下降;缩窄组心肌组织磷酸化ERK1/2蛋白水平术后1周明显增加,4周时达高峰,12周至16周下降至稳定(均P<0.05),总ERK1/2蛋白水平无明显变化。结论:主动脉弓缩窄诱导的压力超负荷可导致左室心肌早期代偿性向心性肥厚向晚期心力衰竭发展。ERK1/2信号转导途径参与压力负荷诱导心肌肥厚和心衰的发生发展过程,并可能通过调控心肌细胞凋亡实现保护作用。
AIM： To explore the changes in extracellular regulated protein kinase （ERK1/2） in the hyper- trophic myocardium induced by pressure overload at the different time courses and to determine the molecular mechanism in the myocardium from hypertrophy to heart failure. METHODS： C57/BL mice, aged 12 week old, were subjected to sham - operation （SH） or transversing aortic constriction （TAC） to establish left ventricular hypertrophy. Echocardiographic assessments, hemodynamic determination, organ weight measurement, morphological and histological examination were performed at 1,4, 8, 12 and 16 weeks after surgery. Meanwhile mRNA levels of atrial natriuretic peptide （ANP） , α - myosin heavy chain （α-MHC）, bcl- 2 and bax were measured by RT- PCR, and ERK1/2 levels were detected by Western blotting. The animals in SH group were performed the same tests then sacrificed at 16 weeks. RESULTS： （1） Compared to SH group, LVESd, LVEDd, Awsth, Awdth, Pwsth and Pwdth progressively increased after TAC. Meanwhile, ejection fraction （EF%） significantly decreased at 16th week （P 〈 0. 05 ）. LVSP, dp/dtmax and dp/dtmin in TAC group were pro- gressively increased after 4 weeks. From 8 - 12 weeks these parameters maintained stable and then sharply decreased at 16th week （all P 〈 0. 05）. However, LVEDP was statistically increased at 8th week. These echocardiographic and hemodynamic changes indicated a development of LVH and eventually progressing towards to heart failure. （2） Histologically, cardiac collagen measured by percentage of Sirius red positive stained area and apoptosis index showed progressive increases from 4 to 16 weeks. （3） Compared to SH group, mRNA levels of ANP was time - dependently increased while α- MHC and Bcl - 2 were time - dependently decreased. The ratio of Bcl - 2/Bax was decreased. Phosphorylation of ERK1/2 was increased at 4th week, then decreased with age of TAC （ all P 〈 0. 05 ）. CONCLUSION： Pressure - overload induced by TAC results in a development of LVH from early concentric hypertrophy to late eccentric hypertrophy, and eventually toward cardiac dysfunction or heart failure. Those changes are associated with increase in cell size and cardiac fibrosis. ERK1/2 signaling pathway may involve in the regulation of myocardial cell apoptosis in hypertrophic and failure heart.
出处
《中国病理生理杂志》
CAS
CSCD
北大核心
2010年第2期209-215,共7页
Chinese Journal of Pathophysiology
基金
国家自然科学基金资助项目(No.30760263)
新疆维吾尔自治区重大专项基金资助项目(No.200733146)
关键词
细胞外信号调节激酶类
主动脉弓缩窄
压力负荷
左室肥大
Extracellular signal -regulated kinases
Aortic arch coarctation
Pressure overload
Left ventricular hypertrophy
