Activated polymorphonuclear leukocytes induce cardiomyocyte apoptosis and the protective effects of carvedilol.
Previous studies have shown that ischemia and reperfusion are potent stimuli for eliciting cardiomyocyte apoptosis, and that polymorphonuclear leukocytes (PMNs) are involved in the development of myocardial injury induced by ischemia and reperfusion. The present study examined whether PMN could directly induce cardiomyocyte apoptosis and, if so, it possible signal transduction pathways. In addition, we also investigated the effects of carvedilol, a potent antioxidant, on PMN-induced apoptosis. Cultured primary neonatal rat cardiomyocytes were exposed to PAF-activated PMNs at concentrations of 10(5), 3 x 10(5) and 10(6) cells/well for 48 h. Multiple detecting techniques, including electron microscopy, DNA gel electrophoresis. TUNEL assay and flow cytometry were used to identify myocyte apoptosis. All of these techniques demonstrated that activated PMNs directly induced cardiomyocyte apoptosis in a concentration-dependent manner, while unactivated PMNs showed no such effect. Activated PMN-induced apoptosis was partially inhibited by SB203580, a specific inhibitor of the p38-MAPK signaling system. Carvedilol (at a dose range of 1-10 mumol/l) significantly prevented activated PMN-induced cardiomyocyte apoptosis. These results suggest that PMNs, when activated, directly induce cardiomyocyte apoptosis and that the p38-MAPK signaling pathway might be involved in this process. Carvedilol may prevent PMN-induced apoptosis possibly because of its antioxidant properties.
Dun
Y
Y
Laboratory of Cardiovascular Physiology, Shanxi Medical University, Taiyuan, P.R. China.
Zhi
J M
JM
Sun
H Y
HY
Zhao
R R
RR
Zhao
Z Q
ZQ
D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D002478:Cells, Cultured; D053938:DNA Fragmentation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry / Q000379:methods; D007093:Imidazoles / Q000494:pharmacology; D020287:In Situ Nick-End Labeling / Q000379:methods; D008854:Microscopy, Electron; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D032383:Myocytes, Cardiac / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects* / Q000648:ultrastructure; D010972:Platelet Activating Factor / Q000494:pharmacology*; D011412:Propanolamines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases
D000975:Antioxidants; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010972:Platelet Activating Factor; D011412:Propanolamines; D011725:Pyridines; D000077261:Carvedilol; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580