Inhibition of apoptosis-regulated signaling kinase-1 and prevention of congestive heart failure by estrogen.
BACKGROUND
Epidemiological studies have shown gender differences in the incidence of congestive heart failure (CHF); however, the role of estrogen in CHF is not known. We hypothesize that estrogen prevents cardiomyocyte apoptosis and the development of CHF.


RESULTS
17Beta-estradiol (E2, 0.5 mg/60-day release) or placebo pellet was implanted subcutaneously into male G alpha q transgenic (Gq) mice. After 8 weeks, E2 treatment decreased the extent of cardiac hypertrophy and dilation and improved contractility in Gq mice. E2 treatment also attenuated nicotinamide adenine dinucleotide phosphate oxidase activity and superoxide anion production via downregulation of Rac1. This correlated with reduced apoptosis in cardiomyocytes of Gq mice. The antioxidative properties of E2 were also associated with increased expression of thioredoxin (Trx), Trx reductases, and Trx reductase activity in the hearts of Gq mice. Furthermore, the activation of apoptosis signal-regulating kinase 1 and its downstream effectors, c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, in the hearts of Gq mice was reduced by long-term E2 treatment. Indeed, E2 (10 nmol/L)-treated cardiomyocytes were much more resistant to angiotensin II-induced apoptosis. These antiapoptotic and cardioprotective effects of E2 were blocked by an estrogen receptor antagonist (ICI 182,780) and by a Trx reductase inhibitor (azelaic acid).


CONCLUSIONS
These findings indicate that long-term E2 treatment improves CHF by antioxidative mechanisms that involve the upregulation of Trx and inhibition of Rac1-mediated attenuated nicotinamide adenine dinucleotide phosphate oxidase activity and apoptosis signal-regulating kinase 1 /c-Jun N-terminal kinase/p38 mitogen-activated protein kinase-mediated apoptosis. These results suggest that estrogen may be a useful adjunctive therapy for patients with CHF.
Satoh
Minoru
M
Vascular Medicine Research Unit, Brigham and Women's Hospital and Harvard Medical School, Cambridge, MA 02139, USA.
Matter
Christian M
CM
Ogita
Hisakazu
H
Takeshita
Kyosuke
K
Wang
Chao-Yung
CY
Dorn
Gerald W
GW
Liao
James K
JK
D000098:Acetophenones / Q000494:pharmacology; D000804:Angiotensin II / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002311:Cardiomyopathy, Dilated / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D048429:Cell Size; D003600:Cytosol / Q000201:enzymology; D003998:Dicarboxylic Acids / Q000494:pharmacology; D004343:Drug Implants; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D000077267:Fulvestrant; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics; D006333:Heart Failure / Q000209:etiology / Q000517:prevention & control*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000037:antagonists & inhibitors* / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D013481:Superoxides / Q000032:analysis; D054481:Thioredoxin Reductase 1; D054482:Thioredoxin Reductase 2; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein
D000098:Acetophenones; D003998:Dicarboxylic Acids; D004343:Drug Implants; D020847:Estrogen Receptor Modulators; D008565:Membrane Proteins; D009479:Neuropeptides; C484602:Rac1 protein, mouse; C515559:Txn1 protein, mouse; C516112:Txn2 protein, mouse; C516113:Txn2 protein, rat; D013481:Superoxides; D000804:Angiotensin II; D000077267:Fulvestrant; D004958:Estradiol; D013879:Thioredoxins; C056165:acetovanillone; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; D054481:Thioredoxin Reductase 1; D054482:Thioredoxin Reductase 2; D013880:Thioredoxin-Disulfide Reductase; C516125:Txnrd1 protein, mouse; C516126:Txnrd1 protein, rat; C516128:Txnrd2 protein, mouse; C516129:Txnrd2 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; C010038:azelaic acid