Carvedilol attenuates CPB-induced apoptosis in dog heart: regulationof Fas/FasL and caspase-3 pathway.
OBJECTIVE
To evaluate the effects of Carvedilol on cardiopulmonary bypass (CPB)-induced myocardiocyte apoptosis and its effects on regulation of Fas, FasL expression, caspase-3 activity and oxidative stress in the left ventricle (LV) in this setting.


METHODS
Ten adult dogs undergoing conventional hypothermic CPB were randomly divided into control and Carvedilol treated groups (n = 5, respectively). Dogs in Carvedilol treated group received a bolus of Carvedilol (1 mg/kg) intravenously and a maintenance dosage of Carvedilol (3 micro g.min(-1).kg(-1)) for 3 hours after the reperfusion of the heart. Dogs in control group received no Carvediolol. LV samples were obtained before, during and 3 hours after CPB. In situ nick end-labeling (TUNEL) technique was used to detect the apoptotic cells. The expressions of Fas and FasL were detected immunohistochemically and quantified by fluorescence activated cell sorting (FACS). The activity of caspase-3 enzyme and malondialdehyde (MDA) level were measured by cleavage of Z-DEVD-AMC substrate and thiobarbituric acid reactive substance (TBARS) method, respectively.


RESULTS
Before and during CPB, all the parameters were not significantly different intra- or between groups (P > 0.05). After CPB, these parameters in both groups were significantly elevated compared with those of before and during CPB (P < 0.028, respectively). However, the number of apoptotic cells in Carvedilol treated group was significantly decreased compared with that of the control group (P < 0.021). The expressions of Fas and FasL were significantly downregulated by Carvedilol (P < 0.001 and 0.003, respectively). The caspase-3 activity and the content of MDA in the Carvedilol treated group was also significantly reduced (P < 0.026 and 0.005, respectively).


CONCLUSIONS
Carvedilol significantly reduces CPB-induced cardiomyocyte apoptosis in dog hearts and the reduction of cardiomyocyte apoptosis is associated with downregulation of Fas and FasL expression, inhibition of caspase-3 activity and oxidative stress in LV.
Zhang
Shunye
S
Department of Cardiovascular Surgery, Shanxi Cardiovascular Hospital, Taiyuan 030024, China.
Sun
Zongquan
Z
Liu
Lixin
L
Hasichaonu
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D002227:Carbazoles / Q000494:pharmacology*; D002315:Cardiopulmonary Bypass; D000077261:Carvedilol; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D004285:Dogs; D015536:Down-Regulation; D053222:Fas Ligand Protein; D005260:Female; D020287:In Situ Nick-End Labeling; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology*; D015398:Signal Transduction; D019014:fas Receptor / Q000378:metabolism*
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D011412:Propanolamines; D019014:fas Receptor; D000077261:Carvedilol; D053148:Caspase 3; D020169:Caspases