Reduction of apoptosis and preservation of mitochondrial integrity under ischemia/reperfusion injury is mediated by estrogen receptor β.
BACKGROUND
Estrogen improves cardiac recovery after ischemia/reperfusion (I/R) by yet incompletely understood mechanisms. Mitochondria play a crucial role in I/R injury through cytochrome c-dependent apoptosis activation. We tested the hypothesis that 17β-estradiol (E2) as well as a specific ERβ agonist improve cardiac recovery through estrogen receptor (ER)β-mediated mechanisms by reducing mitochondria-induced apoptosis and preserving mitochondrial integrity.


METHODS
We randomized ovariectomized C57BL/6N mice 24h before I/R to pre-treatment with E2 or a specific ERβ agonist (ERβA). Isolated hearts were perfused for 20min prior to 30min global ischemia followed by 40min reperfusion.


RESULTS
Compared with controls, ERβA and E2 treated groups showed a significant improvement in cardiac recovery, i.e. an increase in left ventricular developed pressure, dP/dtmax and dP/dtmin. ERβA and E2 pre-treatment led to a significant reduction in apoptosis with decreased cytochrome c release from the mitochondria and increased mitochondrial levels of anti-apoptotic Bcl2 and ACAA2. Protein levels of mitochondrial translocase inner membrane (TIM23) and mitochondrial complex I of respiratory chain were increased by ERβA and E2 pre-treatment. Furthermore, we found a significant increase of myosin light chain 2 (MLC2) phosphorylation together with ERK1/2 activation in E2, but not in ERβA treated groups.


CONCLUSIONS
Activation of ERβ is essential for the improvement of cardiac recovery after I/R through the inhibition of apoptosis and preservation of mitochondrial integrity and can be a achieved by a specific ERβ agonist. Furthermore, E2 modulates MLC2 activation after I/R independent of ERβ.
Institute of Gender in Medicine & Center for Cardiovascular Research, Charité-Universitaetsmedizin, Hessische Str. 3-4, 10115 Berlin, Germany.|DZHK (German Center for Cardiovascular Research), partner site Berlin, Berlin, Germany.
Carola
C
Schubert
Institute of Gender in Medicine & Center for Cardiovascular Research, Charité-Universitaetsmedizin, Hessische Str. 3-4, 10115 Berlin, Germany.|Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
Valeria
V
Raparelli
Max-Delbrück-Center for Molecular Medicine Berlin-Buch, Berlin, Germany.
Christina
C
Westphal
Institute of Gender in Medicine & Center for Cardiovascular Research, Charité-Universitaetsmedizin, Hessische Str. 3-4, 10115 Berlin, Germany.|DZHK (German Center for Cardiovascular Research), partner site Berlin, Berlin, Germany.
Elke
E
Dworatzek
Klinik für Kardiovaskuläre Chirurgie, Universitätsklinikum Düsseldorf, Düsseldorf, Germany.
George
G
Petrov
Institute of Gender in Medicine & Center for Cardiovascular Research, Charité-Universitaetsmedizin, Hessische Str. 3-4, 10115 Berlin, Germany.|DZHK (German Center for Cardiovascular Research), partner site Berlin, Berlin, Germany.
Georgios
G
Kararigas
Institute of Gender in Medicine & Center for Cardiovascular Research, Charité-Universitaetsmedizin, Hessische Str. 3-4, 10115 Berlin, Germany.|DZHK (German Center for Cardiovascular Research), partner site Berlin, Berlin, Germany.
Vera
V
Regitz-Zagrosek
Apoptosis; Estrogen receptor β; Ischemia/reperfusion; Mitochondria; Myosin light chain
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