Abstract 869: Inhibition of Apoptosis and Prevention of Congestive Heart Failure by Estrogen in Gq Transgenic Mice are Mediated by Upregulation of Thioredoxin
Background: Estrogen exerts numerous effects on the cardiovascular system. Recent studies suggest that estrogen may prevent the development of cardiac hypertrophy and its transition into congestive heart failure (CHF). However, the precise mechanism by which estrogen prevents the development of CHF is not known. Using the Gq transgenic mice, which is a genetic model of cardiac hypertrophy that transitions into CHF, we investigated the effects of estrogen on the development of CHF.
Methods and Results: 17beta-estradiol (E2, 0.5 mg/60-day release) or placebo pellet was implanted subcutaneously into male 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 NADPH 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 due, in part, to increased expression of thioredoxin (Trx), Trx reductases (TrxRD) and TrxRD activity in the hearts of Gq mice. Apoptosis signal-regulating kinase 1 (ASK1) and its downstream effectors, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), were activated in the hearts of Gq mice and reduced by long-term E2 treatment. In vitro, E2 (10 nmol/L)-treated cardiomyocytes were more resistant to hydrogen peroxide-induced apoptosis. These cardioprotective effects were blocked by an estrogen receptor antagonist, ICI 182,780, and by TrxRD inhibitor, azelaic acid.
Conclusions: These findings indicate that long-term E2 treatment improves CHF by antioxidative mechanisms involving the upregulation of thioredoxin and inhibition of Rac1-mediated NADPH oxidase activity and ASK1/JNK/p38MAPK-mediated apoptosis. These results suggest that estrogen may be a useful therapeutic agent for preventing the development of CHF.