Downregulation of survival signalling pathways and increased apoptosis in the transition of pressure overload-induced cardiac hypertrophy to heart failure

作者：Li Xiao Mei; Ma Yi Tong^*; Yang Yi Ning; Liu Fen; Chen Bang Dang; Han Wei; Zhang Jian Fa; Gao Xiao Ming

来源：CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, 2009, 36(11): 1054-1061.

DOI：10.1111/j.1440-1681.2009.05243.x

• Akt
• apoptosis
• extracellular signal-regulated kinase 1
• 2
• glycogen synthase kinase 3 beta
• left ventricular hypertrophy

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.

• 出版日期2009-11
• 单位新疆医科大学