| Background and Objectives It has recently been confirmed that the number of apoptotic myocytes is increased in myocardium obtained from experimental animal models of congestive heart failure (CHF) as well as patiens with CHF. Cardiomyocyte apoptosis may play an important role in the pathogenesis of CHF. But the relationship between apoptosis in cardie myocytes and cardiac dysfunction, the molecular mechanisms and significances of apoptosis after myocardial infarction (MI) have not fully been understood. The transcription factor nuclear factor-KB (NF-KB) may play a pivotal role in the initiation and the coordination of genes transcription. It was reported that activation of NF-KB is involved in apoptosis, but its certain role and mechanism in Cardiomyocyte apoptosis in failure heart is to be determine. Clinical trails have demonstrated that long-term treatment with carvedilol (CAR), a new p-adrenoceptor blocker, nonselectively antagonized β1-,β2- and α 1-receptor, improved heart function and prognosis in patients with CHF. The purposes of this study are to determine the patterns of the activation of transcription factors (NF-KB and AP-1) and their importance and relationship to Cardiomyocyte apoptosis, and to study the novel mechanisms of carvedilol in treatment of CHF by investigating the changes of hemodyanmics, ventricular remodeling, cardiac myocyte apoptosis and expression of apoptosis-associated genes, the nuclear DNA binding activity of NF-KB and AP-1, and intervention effects of carvedilol in rats at different phases after MI.Materials and Methods Rats of MI, induced by the left coronary arteryin\Lligation in male waistar rats, were randomly divided into 8 groups: 2-week group (MI2w group, ?7), 4-week group (MLtw group, ?10), 8-week group (MIgw group, H=10), carvedilol at a higher dose group (CAR group, 60mg.kg~1.day"1 X 7-week, ?10) and a lower dose group (LCAR group, 6mg.kg"'.day"1 X 7-week, n=7), metoprolol at a higher dose group (MET group, lOOmg.kg"1.day"1 X 7-week, ?10) and a lower dose group (LMET group, lOmg.kg^.day"1 X 7-week , ?8), and terazosin group (TER group, 1 Omg.kg"1.day'1 X 7-week, ?7). The sham-operated rats were randomly divided into 3 groups: 2-week group (SE^w group, ?9), 4-week group (SRjw group, ?8), 8-week group (SHgw group, n=10), served as controls. The changes of left ventricular weight/body weight (LVW/BW), right ventricular weight/body weight (RVW/BW), hemodyanmics, cardiac myocyte apoptosis index, expression of Fas, FasL and Bcl-2, the concentration of total antioxidation capacity (TAOC) and malondialdehyde (MDA), the levels of inhibitory KB protein (1KB)- a , the nuclear DNA binding activity of NF-KB and AP-1 in left ventricular tissue were measured.Results Compared with corresponding SH groups, RVW/BW and LVEDP were significantly increased in all MI groups, while left ventricular ?dp/dtmax and mean arterial pressure decreased. There were progressive increases in the cardiac myocyte apoptosis index, the expression of Fas and FasL, the concentration of MDA, the activity of NF-KB, and decreases in the concentration of TAOC and expression of 1KB- a after MI. The nuclear DNA binding activity of AP-1 were higher, and expression of Bcl-2 were lower in Ml2\v group, Ml4w group and MIgw group than in corresponding SH groups. Both carvedilol and metoprolol decreased RVW/BW and LVEDP, apoptosis index, the concentration of MDA and expression of Fas, and increased ?dp/dtmax, but the effects of metoprolol were lower. In CAR group, but not MET group, the levels of TAOC and mRNA of Bcl-2 were increased, proteinIV-* Bexpression of FasL and 1KB- a , the activity of NF-KB were decreased. There were no differences in LVEDP, 眃p/dtmax, apoptosis index, expression of apoptosis-associated genes, the levels of TAOC, MDA and 1KB- a , the levels of inhibitory KB (1KB)- a , the nuclear DNA binding activity of NF-KB and AP-1 between TER group and MIgw group. A dose-dependent effect of CAR on LVEDP, 眃p/dtmax, the level o...
|
PDF Full Text Request