Acute postischemic treatment with estrogen receptor-α agonist or estrogen receptor-β agonist improves myocardial recovery

Vornehm, Nicholas D.; Wang, Meijing; Abarbanell, Aaron; Herrmann, Jeremy; Weil, Brent; Tan, Jiangjing; Wang, Yue; Kelly, Megan; Meldrum, Daniel R.

doi:10.1016/j.surg.2009.04.026

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Volume 146, Issue 2 , Pages 145-154, August 2009

Acute postischemic treatment with estrogen receptor-α agonist or estrogen receptor-β agonist improves myocardial recovery

Nicholas D. Vornehm, MS
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
Meijing Wang, MD
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
Aaron Abarbanell, MD
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
Jeremy Herrmann, MD
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
Brent Weil, MD
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
Jiangjing Tan, MD
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
Yue Wang, PhD
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
Megan Kelly, MS
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
Daniel R. Meldrum, MD
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
- Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN
- Center for Immunobiology, Indiana University School of Medicine, Indianapolis, IN
- Clarian Cardiovascular Surgery, Indiana University School of Medicine, Indianapolis, IN
- Reprint requests: Daniel R. Meldrum, MD, 635 Barnhill Drive MS 2017, Indianapolis, IN 46202.

Accepted 17 April 2009.

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-β-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-α agonist (4,4',4''-[4-propyl-(1H)-pyrazole-1,3,5-triyl]tris-phenol [PPT]) or the selective ER-β 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)-α, interleukin (IL)-1β, 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-α or IL-1β. However, higher levels of myocardial VEGF were noted in the PPT-treated group compared with controls.

Conclusion

Both ER-α and ER-β 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.