Estrogen regulates histone deacetylases to prevent cardiac hypertrophy.
Estrogen regulates histone deacetylases to prevent cardiac hypertrophy.
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DOI：
10.1091/mbc.e13-08-0444
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发表时间：
2013-12
影响因子：
3.3
通讯作者：
Levin ER
中科院分区：
文献类型：
--
作者：
Pedram A;Razandi M;Narayanan R;Dalton JT;McKinsey TA;Levin ER
Angiotensin II stimulation of HDAC2 production, phosphorylation by CK2, and resulting modulation of target genes, which promote cardiac hypertrophy, are opposed by estrogen/ERβ. Angiotensin II also represses class II HDAC4 and 5 production and stimulates their phosphorylation, which expels them from the nucleus, and estrogen prevents this. The development and progression of cardiac hypertrophy often leads to heart failure and death, and important modulators of hypertrophy include the histone deacetylase proteins (HDACs). Estrogen inhibits cardiac hypertrophy and progression in animal models and humans. We therefore investigated the influence of 17-β-estradiol on the production, localization, and functions of prohypertrophic (class I) and antihypertrophic (class II) HDACs in cultured neonatal rat cardiomyocytes. 17-β-Estradiol or estrogen receptor β agonists dipropylnitrile and β-LGND2 comparably suppressed angiotensin II–induced HDAC2 (class I) production, HDAC-activating phosphorylation, and the resulting prohypertrophic mRNA expression. In contrast, estrogenic compounds derepressed the opposite effects of angiotensin II on the same parameters for HDAC4 and 5 (class II), resulting in retention of these deacetylases in the nucleus to inhibit hypertrophic gene expression. Key aspects were confirmed in vivo from the hearts of wild-type but not estrogen receptor β (ERβ) gene–deleted mice administered angiotensin II and estrogenic compounds. Our results identify a novel dual regulation of cardiomyocyte HDACs, shown here for the antihypertrophic sex steroid acting at ERβ. This mechanism potentially supports using ERβ agonists as HDAC modulators to treat cardiac disease.
