| Effects of carvedilol therapy on cardiomyocyte apoptosis andsarcoplasmic reticulum Ca2~ ATPase activity and geneexpression in congestive heart failureAbstractRecently multiple central clinical trials have shown that long-term treatment with ~3-blockers in patients with congestive heart failure (CHF) was favorable to improve cardiac function, reduce all-cause mortality and the risk of cardiovascular hospitalization. It suggested that the third-generation nonselective f3-blocker, carvedilol, may be more prognostic effective than selective ~31-blockers. However, up to now, the exact mechanism of f3-blocker therapy of CHF remains unclear. It is well known, that the contraction and relaxation of cardiomyocytes are regulated by intracellular Ca2~ which are controlled by the sarcoplasmic reticulum. Functional status and expression level of SERCA2a and RyR2 are closely correlated with cardiac function. Besides, Fas, Bax and bcl-2, as important factors regulate myocyte death and survival, Cardiomyocytes loss due to apoptosis may play an important role in the pathogenesis of CHF. It is uncertain whether carvedilol have effects on SERCA2a activity and RyR2 density as well as their genes expression. The precise evidence to identify that carvedilol may prevent cardiomyocyte apoptosis is to be determined. Even carvedilol was proved very effective in treatment of CHF in western countries, but It is unknown how about the clinic effects and tolerability of high-dose carvedilol in Chinese patients with CHF. This study was designed to evaluate effects of carvedilol on SERCA2~ activity, RyR2 density and their genes expression, cardiomyocyte apoptosis and related protein levels of Fas, bcl-2 and Bax in rats with chronic cardiac insufficiency induced by coronary artery ligation, and the effects on ventricular remodeling and serum level of sFas in patients with CHF due to DCM, to explore the mechanism of action of carvedilol and its clinical effects and the tolerability inChinese patents with CHF.The results are as follow:(l) Abnormality of hemodynamic, hiStOpathology and ultrastructUre wereobserved in rats after coronary anery ligation 10 weeks, and improvedmarkedly by 1ong-term carvedilol intervelition.(2) The activity, mRNA and prOtein expression of SERCA,.' the densityand MA expression level of RyRz in rats with chronic cardiac dysfunctiondecreased significantly (P<0.0l).(3) The activity mRNA and protein exPression level of SERCAz.' thedensity and InRNA expression of RyR2 in rats treated with carvedilol increaseddose-relatedly, and no change was observed in the terazosin grouP.(4) The rate of cardiomyocyte aPoptosis, protein levels of Fas and Bax inrats with cardiac dysfunction increased significantly while the protein level ofbcl-2 decreased. The incidence of aPoptosis, protein leve1s of Fas and Baxwere higher in infarction borders than remote regions.(5) Carvedilol intervention reduced myocyte aPoptosis, protein levels ofFas and Bax, and improved protein level of bcl-2 in rats with chronic cardiacdysfunction dose-relatedly(6) The activity of SERCA2. was strongly correlated with the rate ofcardiomyocyte aPoptosis, +dP/dtm.. and -dP/dk,. respectively (re - 0.8l4, 0.69l,0.645, P<0.00l). There was a positive correlation between the density of RyR2and +dP/dtmax(re 0.496, P<0.00l).(7) Heart function, LVEF, LVFS, SV improved significantly' and HR,LVSD and D/T reduced in patieats with CHF due to DCM after treated withcarvedilol fOr a long-term.(8) The mean to1erated dose of carvedilol in the stUdy was 28.75 mg dailywtth a range of l0 to 40 mg daily.(9) Seruzn leve1 of sFas in patenis wth DCM increased significanly, andit was higher in patients with LVEF>35% than that of <35%. The level of sFasin patients treated with carvedilol for 3 months decreased to normal level.IVIt is concluded that:(1)Abnormality of SERCA23 activity and RyR2 density may play an important role in myocardial dysfunction.(2)Abnormality of gene expre...
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