Transgenic overexpression of Hdac3 in the heart produces increased postnatal cardiac myocyte proliferation but does not induce hypertrophy
Transgenic overexpression of Hdac3 in the heart produces increased postnatal cardiac myocyte proliferation but does not induce hypertrophy
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DOI：
10.1074/jbc.m803686200
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发表时间：
2008-09-26
影响因子：
4.8
通讯作者：
Epstein, Jonathan A.
中科院分区：
文献类型：
--
作者：
Trivedi, Chinmay M.;Lu, Min Min;Epstein, Jonathan A.
I类和II类组蛋白去乙酰化酶（HDAC）在调节心脏发育、形态发生和肥大反应中起重要作用。虽然已经报道了Hdac 1和Hdac 2（I类HDAC）在心脏增生、生长和肥大反应中的作用，但Hdac 3（另一种I类HDAC）在心脏中的作用还没有得到很好的研究。在这里，我们报告，心肌细胞特异性过表达的Hdac 3在小鼠出生时心脏畸形的结果。hdac 3过表达可导致新生儿心室肌增厚，尤其是室间隔增厚，并导致两个心室腔缩小。我们的数据表明，增加心肌厚度在Hdac 3转基因（Hdac 3-Tg）小鼠是由于增加心肌细胞增生没有肥大。Hdac 3过表达抑制几种细胞周期蛋白依赖性激酶抑制剂，包括Cdkn 1a，Cdkn 1b，Cdkn 1c，Cdkn 2b和Cdkn 2c。与先前报道的Hdac 2-Tg小鼠不同，Hdac 3-Tg小鼠在3月龄时没有发生心脏肥大。此外，与野生型同窝仔相比，Hdac 3过表达并没有增加异丙肾上腺素诱导的心脏肥大。这些发现确定Hdac 3作为一种新的调节心肌细胞增殖在心脏发育过程中。
Class I and II histone deacetylases (HDACs) play vital roles in regulating cardiac development, morphogenesis, and hypertrophic responses. Although the roles of Hdac1 and Hdac2, class I HDACs, in cardiac hyperplasia, growth, and hypertrophic responsiveness have been reported, the role in the heart of Hdac3, another class I HDAC, has been less well explored. Here we report that myocyte-specific overexpression of Hdac3 in mice results in cardiac abnormalities at birth. Hdac3 overexpression produces thickening of ventricular myocardium, especially the interventricular septum, and reduction of both ventricular cavities in newborn hearts. Our data suggest that increased thickness of myocardium in Hdac3-transgenic (Hdac3-Tg) mice is due to increased cardiomyocyte hyperplasia without hypertrophy. Hdac3 overexpression inhibits several cyclin-dependent kinase inhibitors, including Cdkn1a, Cdkn1b, Cdkn1c, Cdkn2b, and Cdkn2c. Hdac3-Tg mice did not develop cardiac hypertrophy at 3 months of age, unlike previously reported Hdac2-Tg mice. Further, Hdac3 overexpression did not augment isoproterenol-induced cardiac hypertrophy when compared with wild-type littermates. These findings identify Hdac3 as a novel regulator of cardiac myocyte proliferation during cardiac development.