ER-beta Mediates 17 beta-Estradiol Attenuation of HIV-1 Tat-Induced Apoptotic Signaling

作者：Adams Sheila M^*; Aksenova Marina V; Aksenov Michael Y; Mactutus Charles F; Booze Rosemarie M

来源：Synapse, 2010, 64(11): 829-838.

DOI：10.1002/syn.20793

• neuroprotection
• estrogen
• cell death
• AIDS

The protective actions of estrogen have been well evaluated in various models of neurodegeneration. These neuroprotective mechanisms may include a direct neuronal antiapoptotic effect as estrogen modulates actions of key regulators of the mitochondrial/intrinsic apoptotic cascade. We tested the ability of estrogen to protect against apoptotic signaling in cortical cell cultures exposed to Tat 1-86 (50 nM), and additionally, whether the beneficial actions of estrogen involved an estrogen receptor sensitive mechanism. We demonstrated that estrogen pretreatment significantly delayed Tat-induced cell death in primary cortical cultures. Pretreatment with 17 beta-estradiol (10 nM) attenuated the increased expression of antiapoptotic protein Bcl-2, proapoptotic protein Bax and activation of caspases linked to mitochondrial apoptotic pathway following Tat exposure. In addition, select components of apoptotic pathway signaling appear more sensitive to estrogen receptor (ER) activation, as the addition of ER antagonist ICI 182780 reversed estrogen downregulation of Bax and caspase 3, while estrogen effects on Tat-induced Bcl-2 and caspase 9 expression were maintained. Moreover, the addition of preferential ER alpha and ER beta antagonists (MPP dihydrochloride and PHTPP) indicated that estrogen effects on caspase 3 may be mediated by both receptor subtypes, whereas, was more involved in estrogen effects on Bax. Our data suggest that estrogen intervenes against HIV-1 Tat-induced cortical neuronal dysfunction via intersecting mitochondria] apoptotic pathway signaling in an ER-sensitive manner. Synapse 64:829-838, 2010.

• 出版日期2010-11