Acute postischemic treatment with estrogen receptor-alpha agonist or estrogen receptor-beta agonist improves myocardial recovery.
BACKGROUND
After ischemia/reperfusion (I/R) injury, female hearts demonstrate improved functional recovery compared with male, which suggests a protective role for estrogen. Acute postischemic treatment with 17-beta-estradiol (E2) attenuates myocardial dysfunction. However, it is unknown by which estrogen receptor (ER) E2 mediates this acute cardioprotection during I/R. Therefore, we hypothesize that postischemic infusion of the selective ER-alpha agonist (4,4',4''-[4-propyl-(1H)-pyrazole-1,3,5-triyl]tris-phenol [PPT]) or the selective ER-beta agonist (2,3-bis(4-hydroxyphenyl)-propionitrile [DPN]) will improve myocardial function after I/R injury.


METHODS
Isolated, perfused hearts (Langendorff) from adult male rats were subjected to 25 minutes of ischemia followed by 40 minutes of reperfusion. Hearts (n = 4-6 per group) were randomly infused with either perfusate, PPT or DPN at 1, 10, or 100 nmol/L throughout reperfusion. After I/R, heart tissue was analyzed for tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, vascular endothelial growth factor (VEGF), and lactate dehydrogenase (LDH).


RESULTS
Postischemic treatment with 10 nmol/L of PPT significantly improved myocardial function. Additionally, 10 or 100 nmol/L of DPN significantly increased myocardial functional recovery after I/R injury, with maximum benefit at the 10 nmol/L dose. A trend toward lower levels of LDH was noted in DPN- and PPT-treated groups after I/R injury. Neither PPT nor DPN affected myocardial production of TNF-alpha or IL-1beta. However, higher levels of myocardial VEGF were noted in the PPT-treated group compared with controls.


CONCLUSIONS
Both ER-alpha and ER-beta are involved in mediating E2-induced rapid cardioprotection after I/R injury. Advancing our understanding of both ER subtypes may be useful for the development of novel strategies that may benefit both males and females in response to myocardial ischemia.
Vornehm
Nicholas D
ND
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Wang
Meijing
M
Abarbanell
Aaron
A
Herrmann
Jeremy
J
Weil
Brent
B
Tan
Jiangjing
J
Wang
Yue
Y
Kelly
Megan
M
Meldrum
Daniel R
DR
D000818:Animals; D003326:Coronary Circulation; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000502:physiology; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000502:physiology; D005260:Female; D066298:In Vitro Techniques; D053583:Interleukin-1beta / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology*; D010636:Phenols / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D016277:Ventricular Function, Left; D011422:Propionates
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D053583:Interleukin-1beta; D007770:L-Lactate Dehydrogenase; D009570:Nitriles; D010636:Phenols; D011720:Pyrazoles; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D011422:Propionates; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol