Downregulation of survival signalling pathways and increased apoptosis in the transition of pressure overload-induced cardiac hypertrophy to heart failure
Downregulation of survival signalling pathways and increased apoptosis in the transition of pressure overload-induced cardiac hypertrophy to heart failure
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DOI：
10.1111/j.1440-1681.2009.05243.x
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发表时间：
2009-11-01
影响因子：
2.9
通讯作者：
Gao, Xiao-Ming
中科院分区：
文献类型：
--
作者：
Li, Xiao-Mei;Ma, Yi-Tong;Gao, Xiao-Ming
采用压力超负荷诱导的P>；从代偿性左心室肥厚向失代偿性心力衰竭转变的模型，阐明心肌细胞凋亡与存活信号之间的时间关系。小鼠接受横动脉缩窄(TAC)或假手术1-16周，并进行超声心动图、导管术和组织学研究。TAC后，心钠素、B型利钠肽、β-肌球蛋白重链(MHC)和转化生长因子-β1的mRNA水平呈时间依赖性增加而α-MHC、肌浆/内质网钙ATPase 2a和Bcl2的mRNA表达降低。Bcl2/Bax比值降低，与末端脱氧核糖核苷酸转移酶介导的dUTP-地高辛缺口末端标记显示心肌细胞凋亡进行性增加相一致。ERK1/2的磷酸化在第4周时增加，但此后下降。Akt的磷酸化水平从8周开始下降，而GSK3β的磷酸化水平从1周到8周升高，然后从12周开始下降。结论：TAC导致早期向心性肥厚和晚期离心性肥厚，最终发展为左心功能不全。这种转变在时间上与细胞大小、纤维化和心肌细胞凋亡的进行性增加有关。ERK1/2、Akt和GSK3β表达下调以及心肌细胞凋亡增强是心肌代偿性肥厚向心力衰竭转变的重要机制。
P> Transition from compensated left ventricular (LV) hypertrophy to decompensated heart failure was characterized using a pressure-overload induced model to elucidate the temporal relationship between cardiomyocyte apoptosis and survival signalling in this transition.Mice were subjected to transverse aortic constriction (TAC) or sham operation for 1-16 weeks and were studied by echocardiography, catheterization and histology. Relevant gene expression and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, Akt and glycogen synthase kinase (GSK)-3 beta were determined.Transverse aortic constriction resulted in myocyte hypertrophy and fibrosis from Week 4 and a progressive increase in left ventricular (LV) dimensions and wall thicknesses with maintained contractile function by Week 12. However, a sharp decline in contractile function and elevated LV end-diastolic pressure from 12 to 16 weeks were observed after TAC, indicating functional decompensation.Following TAC, mRNA levels of atrial natriuretic peptide, B-type natriuretic peptide, beta-myosin heavy chain (MHC) and transforming growth factor-beta 1 were increased time dependently, whereas mRNA expression of alpha-MHC, sarcoplasmic/endoplasmic reticulum calcium ATPase 2a and Bcl-2 were decreased. The ratio of Bcl-2/Bax was decreased and this was consistent with progressively increased myocyte apoptosis demonstrated by terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling staining. Phosphorylation of ERK1/2 was increased by Week 4, but decreased thereafter. Levels of phosphorylated Akt declined from Week 8, whereas GSK3 beta phosphorylation increased from 1 to 8 weeks, then decreased from Week 12 after TAC.In conclusion, TAC resulted in early concentric and late eccentric hypertrophy with eventual development of LV dysfunction. This transition was temporally associated with a progressive increase in cell size, fibrosis and myocyte apoptosis. Downregulation of ERK1/2, Akt and GSK3 beta and enhanced cardiomyocyte apoptosis are implicated as important mechanisms in the transition from compensated hypertrophy to heart failure.