The late phase of ischemic preconditioning induces a prosurvival genetic program that results in marked attenuation of apoptosis.
Although the cardioprotection afforded by the late phase of ischemic preconditioning (PC) in ischemia/reperfusion (I/R) injury has been well studied, it is unknown whether this beneficial effect can be attributed to inhibition of apoptosis. We hypothesized that ischemic PC affords protection by suppressing apoptosis and examined the underlying mechanisms. Myocardial infarction was produced in mice (30-min coronary occlusion). In animals preconditioned 24 h earlier with six 4-min coronary occlusion/4-min reperfusion (O/R) cycles, there was a marked decrease in apoptosis as assessed by three different parameters: hairpin-1 assay, caspase-3 activity, and immunohistochemical analysis of active caspase-3 and cleaved poly (ADP-ribose) polymerase-1 (PARP-1). This protective effect was accompanied by increased expression of multiple antiapoptotic proteins that regulate both the mitochondria-mediated (Bcl-x(L) and Mcl-1) and the death-receptor-mediated (c-FLIP(L) and c-FLIP(S)) pathway of apoptosis and by decreased expression of the proapoptotic protein Bad. This is the first demonstration that the late phase of ischemic PC attenuates cardiac apoptosis after ischemia/reperfusion injury and that this salubrious effect is associated with a complex genetic prosurvival program that results in modulation of several key proteins involved in both the mitochondrial and the death receptor pathways of apoptosis.
Stein
Adam B
AB
Department of Medicine and the Institute of Molecular Cardiology, University of Louisville, 570 S. Preston Street, Louisville, KY 40202-1757, USA.
Bolli
Roberto
R
Guo
Yiru
Y
Wang
Ou-Li
OL
Tan
Wei
W
Wu
Wen-Jian
WJ
Zhu
Xiaoping
X
Zhu
Yanqing
Y
Xuan
Yu-Ting
YT
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000032:analysis / Q000378:metabolism*; D004789:Enzyme Activation; D007150:Immunohistochemistry; D019194:Ischemic Preconditioning; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
C494820:Bad protein, mouse; C494827:Bax protein, mouse; C494812:Bcl2l1 protein, mouse; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506387:Cflar protein, mouse; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3