Activation of the transient receptor potential M2 channel and poly(ADP-ribose) polymerase is involved in oxidative stress-induced cardiomyocyte death.
Overproduction of reactive oxygen species is one of the major causes of cell death in ischemic-reperfusion (I/R) injury. In I/R animal models, electron microscopy (EM) has shown mixed apoptotic and necrotic characteristics in the same cardiomyocyte. The present study shows that H(2)O(2) activates both apoptotic and necrotic machineries in the same myocyte and that the ultrastructure seen using EM is very similar to that in I/R animal studies. The apoptotic component is caused by the activation of clotrimazole-sensitive, NAD(+)/ADP ribose/poly(ADP-ribose) polymerase (PARP)-dependent transient receptor potential M2 (TRPM2) channels, which induces mitochondrial [Na(+)](m) (and [Ca(2+)](m)) overload, resulting in mitochondrial membrane disruption, cytochrome c release, and caspase 3-dependent chromatin condensation/fragmentation. The necrotic component is caspase 3-independent and is caused by PARP-induced [ATP](i)/NAD(+) depletion, resulting in membrane permeabilization. Inhibition of either TRPM2 or PARP activity only partially inhibits cell death, while inhibition of both completely prevents the ultrastructural changes and myocyte death.
Yang
K-T
KT
Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Chang
W-L
WL
Yang
P-C
PC
Chien
C-L
CL
Lai
M-S
MS
Su
M-J
MJ
Wu
M-L
ML
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006861:Hydrogen Peroxide / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D009336:Necrosis; D018384:Oxidative Stress / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism; D050053:TRPM Cation Channels / Q000378:metabolism*
D050053:TRPM Cation Channels; D009243:NAD; D012964:Sodium; D006861:Hydrogen Peroxide; D011065:Poly(ADP-ribose) Polymerases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D002118:Calcium