Estrogen attenuates cardiac ischemia-reperfusion injury via inhibition of calpain-mediated bid cleavage.
Although several studies have shown that the administration of 17beta-estradiol (estrogen) is cardioprotective to ischemia-reperfusion (I/R), the molecular mechanisms are largely unknown. Therefore, we investigated the effects of estrogen on myocardial I/R injury in rat that were sham operated (Sham), ovariectomized (OVX), or ovariectomized and then given estrogen supplementation (OE). Langendorff-perfused rat hearts were subjected to I/R stimuli and the effects of estrogen were examined on cardiac performance. Additionally, we examined the mechanism of estrogen-mediated inhibition of apoptosis. Depression in cardiac contractile function and an increment of calpain activity were observed during I/R in the OVX rats. Estrogen replacement recovered cardiac contractile function and attenuated calpain activity, Bid cleavage, and caspases activities. Through in vitro assay using cardiomyocytes, we demonstrated that addition of H2O2 (100 microM) significantly increased calpain activity, which was attenuated by estrogen. Moreover, calpain activity was inhibited by calpain inhibitors such as ALLN or leupeptin, but not by caspase-8 inhibitor peptide. These results suggest that estrogen protects the heart against I/R injury through the decrease of calpain activity, Bid cleavage and caspase-8 activity. These apoptotic mechanisms may play a critical role on I/R-associated cardiac damage.
Department of Pharmacology, Chonbuk National University Medical School, Jeonju, Chonbuk, Korea.
Soo-Uk
SU
Chae
Ki-Chan
KC
Ha
Cheng-Shi
CS
Piao
Soo-Wan
SW
Chae
Han-Jung
HJ
Chae
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D006861:Hydrogen Peroxide / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D009200:Myocardial Contraction; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010052:Ovariectomy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D051023:BH3 Interacting Domain Death Agonist Protein; C494828:Bax protein, rat; C494816:Bid protein, rat; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C063261:acetylleucyl-leucyl-norleucinal; D004958:Estradiol; D006861:Hydrogen Peroxide; D002154:Calpain; D020169:Caspases