Publications (3)6.21 Total impact
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ABSTRACT: 1. 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. 2. 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)-3β were determined. 3. 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. 4. Following TAC, mRNA levels of atrial natriuretic peptide, B-type natriuretic peptide, β-myosin heavy chain (MHC) and transforming growth factor-β1 were increased time dependently, whereas mRNA expression of α-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 GSK3β phosphorylation increased from 1 to 8 weeks, then decreased from Week 12 after TAC. 5. 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 GSK3β and enhanced cardiomyocyte apoptosis are implicated as important mechanisms in the transition from compensated hypertrophy to heart failure.
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ABSTRACT: To investigate the effects of ischemic postconditioning (IPost) in protecting hypertrophic myocardium subjected to ischemic-reperfusion (I/R) and to study the role of extracellular regulated protein kinase (ERK1/2) in mediating such protection. Transverse aortic constriction (TAC) operation was performed on 12-week-old C57/BL mice to establish left ventricular hypertrophy models. Sixty-four isolated TAC mouse hearts were mounted onto the Langendorff perfusion system and randomly divided into 4 equal group: (1) I/R group undergoing stable perfusion for 30 min, ischemia for 30 min, and re-perfusion for 120 min (an I/R cycle) to cause hypertrophic myocardium I/R injury, (2) IPost group undergoing ischemia for 10s and reperfusion for 10s, totally 3 cycles (60s) before reperfusion for 120 min, (3) I/R+ PD98059 (an ERK1/2 inhibitor) group undergoing perfusion of Krebs-Henseleit (KH) buffer with PD98059 10(-5)mol/L for 15 min and perfusion of KH buffer without PD98059 at the beginning of re-perfusion, and (4) IPost + PD98059 group undergoing 3 cycles of IPost and perfusion of KH buffer with PD98059 10(-5)mol/L for 15 min at the beginning of re-perfusion. Hemodynamic examination was conducted 120 min after re-perfusion to measure the left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), maximal uprising velocity of left ventricle pressure (dp/dt(max)), and minimal uprising velocity of left ventricle pressure (dp/dt(min)). After the I/R procedure the myocardium of the left ventricle was isolated to detect the infarction size (IS). Western blotting was used to detect the protein expression of extracellular signal-regulated kinase (ERK) 1/2, phosphorylated ERK1/2, Bcl-2, Bax, and mitochondrial and cytosolic cytochrome (Cyt). C. TUNEL was used to detect the apoptotic rate. The LVSP and dp/dt(max) levels of the IPost group were (85 +/- 4) mm Hg and (3811 +/- 230) mm Hg/s, both significantly higher than those of the I/R group [(68 +/- 5) mm Hg and (2830 +/- 230) mm Hg/s respectively, both P < 0.05]. Compared with the I/R group, the protein levels of phosphorylated ERK1/2, Bcl-2, mitochondrial CytC of the IPost group were all significantly higher, the protein levels of Bax and cytosolic CytC, and apoptosis index were significantly lower (all P < 0.05), and the IS was smaller (P < 0.05). I/R + PD98059 showed no effects on the above-mentioned parameters. However, the results of the IPost + PD98059 group showed that in the first 15 min of reperfusion addition of PD98059 reversed all changes observed in the IPost group and eliminated the IPost protection by increasing IS to a level similar to that in the I/R group. IPost has protective effect in hypertrophic myocardium with I/R injury in vitro. ERK1/2 signaling pathway is involved in the protection of IPost by regulating the myocyte apoptosis.
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ABSTRACT: Cardiac rupture is more prevalent in elderly patients with first onset of acute myocardial infarct (MI), but the mechanism remains unexplored. We investigated the differences in the incidence of cardiac rupture and early left ventricular (LV) remodeling following coronary artery ligation between old (12-mo) and young (3-mo) C57Bl/6 male mice and explored responsible mechanisms. The incidence of rupture within 1 wk after MI was significantly higher in old than in young mice (40.7 vs. 18.3%, P = 0.013) despite a similar infarct size in both age groups. Old mice dying of rupture had more severe infarct expansion than young counterparts. Echocardiography and catheterization at day 7 revealed more profound LV chamber dilatation and dysfunction as well as higher blood pressures in aged mice. At day 3 after MI immediately before the peak of rupture occurrence, we observed significantly higher content of type I and III collagen, a greater density of macrophage and neutrophil, and markedly enhanced mRNA expression of inflammatory cytokines in the infarcted myocardium in old than in young mice. Furthermore, a more dramatic increment of matrix metalloproteinase (MMP)-9 activity was found in old than in young infarcted hearts, in keeping with enhanced inflammatory response. Collectively, these results revealed that old mice had a higher risk of post-MI cardiac rupture despite a higher level of collagen content and cross-linking. Enhanced inflammatory response and subsequent increase in MMP-9 activity together with higher blood pressure are important factors responsible for the higher risk of cardiac rupture and more severe LV remodeling in the aged heart following acute MI.
Xinjiang Medical UniversityOuroumtchi, Xinjiang Uygur Zizhiqu, China