Center for Cardiovascular Sciences, Albany Medical College, NY 12208, USA.
Biochem J. 2012 May 15;444(1):105-14. doi: 10.1042/BJ20120152.
VSMCs (vascular smooth muscle cells) dedifferentiate from the contractile to the synthetic phenotype in response to acute vascular diseases such as restenosis and chronic vascular diseases such as atherosclerosis, and contribute to growth of the neointima. We demonstrated previously that balloon catheter injury of rat carotid arteries resulted in increased expression of CaMKII (Ca(2+)/calmodulin-dependent protein kinase) IIδ(2) in the medial wall and the expanding neointima [House and Singer (2008) Arterioscler. Thromb. Vasc. Biol. 28, 441-447]. These findings led us to hypothesize that increased expression of CaMKIIδ(2) is a positive mediator of synthetic VSMCs. HDAC (histone deacetylase) 4 and HDAC5 function as transcriptional co-repressors and are regulated in a CaMKII-dependent manner. In the present paper, we report that endogenous HDAC4 and HDAC5 in VSMCs are activated in a Ca(2+)- and CaMKIIδ(2)-dependent manner. We show further that AngII (angiotensin II)- and PDGF (platelet-derived growth factor)-dependent phosphorylation of HDAC4 and HDAC5 is reduced when CaMKIIδ(2) expression is suppressed or CaMKIIδ(2) activity is attenuated. The transcriptional activator MEF2 (myocyte-enhancer factor 2) is an important determinant of VSMC phenotype and is regulated in an HDAC-dependent manner. In the present paper, we report that stimulation of VSMCs with ionomycin or AngII potentiates MEF2's ability to bind DNA and increases the expression of established MEF2 target genes Nur77 (nuclear receptor 77) (NR4A1) and MCP1 (monocyte chemotactic protein 1) (CCL2). Suppression of CaMKIIδ(2) attenuates increased MEF2 DNA-binding activity and up-regulation of Nur77 and MCP1. Finally, we show that HDAC5 is regulated by HDAC4 in VSMCs. Suppression of HDAC4 expression and activity prevents AngII- and PDGF-dependent phosphorylation of HDAC5. Taken together, these results illustrate a mechanism by which CaMKIIδ(2) mediates MEF2-dependent gene transcription in VSMCs through regulation of HDAC4 and HDAC5.
血管平滑肌细胞（VSMCs）在急性血管疾病（如再狭窄）和慢性血管疾病（如动脉粥样硬化）中从收缩型向合成型表型分化，并促进新生内膜的生长。我们之前的研究表明，大鼠颈动脉球囊损伤导致中膜壁和扩张的新生内膜中 CaMKII（钙/钙调蛋白依赖性蛋白激酶）IIδ（2）的表达增加[House 和 Singer（2008），动脉粥样硬化血栓形成血管生物学 28,441-447]。这些发现使我们假设 CaMKIIδ（2）的表达增加是合成型 VSMCs 的正向介质。组蛋白去乙酰化酶（HDAC）4 和 HDAC5 作为转录共抑制因子发挥作用，并以 CaMKII 依赖性方式进行调节。在本论文中，我们报告说 VSMCs 中的内源性 HDAC4 和 HDAC5 以 Ca（2+）和 CaMKIIδ（2）依赖性方式被激活。我们进一步表明，当 CaMKIIδ（2）的表达受到抑制或 CaMKIIδ（2）活性受到抑制时，AngII（血管紧张素 II）和 PDGF（血小板衍生生长因子）依赖性 HDAC4 和 HDAC5 的磷酸化减少。转录激活因子 MEF2（肌细胞增强因子 2）是 VSMC 表型的重要决定因素，并以 HDAC 依赖性方式进行调节。在本论文中，我们报告说，用离子霉素或 AngII 刺激 VSMCs 可增强 MEF2 结合 DNA 的能力，并增加已建立的 MEF2 靶基因 Nur77（核受体 77）（NR4A1）和 MCP1（单核细胞趋化蛋白 1）（CCL2）的表达。抑制 CaMKIIδ（2）可减弱 MEF2 DNA 结合活性的增加和 Nur77 和 MCP1 的上调。最后，我们表明 HDAC5 在 VSMCs 中受 HDAC4 调节。抑制 HDAC4 的表达和活性可防止 AngII 和 PDGF 依赖性 HDAC5 磷酸化。总之，这些结果说明了 CaMKIIδ（2）通过调节 HDAC4 和 HDAC5 介导 VSMCs 中 MEF2 依赖性基因转录的机制。
