Submitted on September 4, 2007
Accepted on May 19, 2008
Estradiol Abolishes Reduction in Cell Death By the Opioid Agonist Met5-Enkephalin After Oxygen Glucose Deprivation in Isolated Cardiomyocytes From Both Sexes
Matthias Johannes Merkel1*, Lijuan Liu2, Zhiping Cao2, William Packwood3, Patricia D. Hurn4, and Donna M Van Winkle5
1 Anesthesiology & Peri-Operative Medicine, Oregon Health Sciences University, Portland, Oregon, United States; Research Services, Veterans Affair Medical Center Oregon, Portland, Oregon, United States
2 Anesthesiology Services, Veterans Affair Medical Center Oregon, Portland, Oregon, United States
3 Research Services, Veterans Affair Medical Center Oregon, Portland, Oregon, United States
4 Anesthsiology and Peri-Operative Medicine, Oregon Health Sciences University, Portland, Oregon, United States
5 Anesthesiology Services, Veterans Affair Medical Center Oregon, Portland, Oregon, United States; Research Services, Veterans Affair Medical Center Oregon, Portland, Oregon, United States; Anesthesiology & Peri-Operative Medicine, Oregon Health Sciences University, Portland, Oregon, United States
* To whom correspondence should be addressed. E-mail: merkelm{at}ohsu.edu.
Objective. There is evidence for differences in the response to treatment of cardiovascular disease in men and women. In addition, there are conflicting results regarding the effectiveness of pharmacologically induced protection or ischemic preconditioning in females. We investigated whether the ability of Met5-enkephalin (ME) to reduce cell death after oxygen-glucose deprivation (OGD) is influenced by the presence of 17
-estradiol (E2) in a nitric oxide (NO) and estrogen receptor dependent manner. Methods. Postnatal day (PND) 7-8 murine cardiomyocytes from wildtype or inducible NO synthase (iNOS) knockout mice were separated by sex, isolated by collagenase digestion, cultured for 24 hours, and subjected to 90 minutes OGD and 180 minutes reoxygenation at 37°C (n=4-5 replicates). Cell cultures were incubated in E2 for 15 minutes or 24 hours prior to OGD. ME was used to increase cell survival. Cell death was assessed by propidium iodide. More than 300 cells were examined for each treatment. Data are presented as mean ± SEM. Results. In both sexes, ME-induced cell survival was lost in the presence of E2, and the ability of ME to improve cell survival was restored after treatment with the estrogen receptor antagonist, ICI 182,780. Further, iNOS was necessary for ME to increase cell survival following OGD in vitro. Conclusion. We conclude that ME-induced reduction in cell death is abolished by E2 in a sex-independent manner via activation of estrogen receptors, and this interaction is dependent on iNOS.
