细胞可塑性是生物学和疾病的基础。血管平滑肌细胞(SMC)去分化(收缩蛋白的丢失)引发并导致血管病变,例如再狭窄。收缩基因表达受主转录因子支配,血清反应因子(SRF)。与其他组蛋白脱乙酰酶不同,组蛋白脱乙酰酶6(HDAC6)主要位于胞质溶胶中。HDAC6是否调节SRF核活性以前在任何细胞类型中都是未知的。这项研究发现,用tubastatinA选择性抑制HDAC6保留了收缩蛋白(α-平滑肌肌动蛋白),否则该蛋白会被血小板衍生的生长因子-BB减少。TubastatinA还增强了SRF转录(荧光素酶)活性,HDAC6敲低证实了这种作用。有趣的是,HDAC6抑制增加myocardin相关转录因子A(MRTF-A)的乙酰化和总蛋白,一种转录共激活因子,已知可以从细胞溶质转移到细胞核,从而激活SRF。始终如一,HDAC6与MRTF-A共免疫沉淀体内研究表明,tubstatinA治疗受损的大鼠颈动脉可减轻新生内膜病变,已知主要由去分化的SMC形成。本报告首次显示HDAC6对MRTF-A/SRF轴和SMC可塑性的调节,从而为血管病变的干预开辟了新的视角。
Cellular plasticity is fundamental in biology and disease. Vascular smooth muscle cell (SMC) dedifferentiation (loss of contractile proteins) initiates and perpetrates vascular pathologies such as restenosis. Contractile gene expression is governed by the master transcription factor, serum response factor (SRF). Unlike other histone deacetylases, histone deacetylase 6 (HDAC6) primarily resides in the cytosol. Whether HDAC6 regulates SRF nuclear activity was previously unknown in any cell type. This study found that selective inhibition of HDAC6 with tubastatin A preserved the contractile protein (alpha-smooth muscle actin) that was otherwise diminished by platelet-derived growth factor-BB. Tubastatin A also enhanced SRF transcriptional (luciferase) activity, and this effect was confirmed by HDAC6 knockdown. Interestingly, HDAC6 inhibition increased acetylation and total protein of myocardin-related transcription factor A (MRTF-A), a transcription co-activator known to translocate from the cytosol to the nucleus, thereby activating SRF. Consistently, HDAC6 co-immunoprecipitated with MRTF-A. In vivo studies showed that tubastatin A treatment of injured rat carotid arteries mitigated neointimal lesion, which is known to be formed largely by dedifferentiated SMCs. This report is the first to show HDAC6 regulation of the MRTF-A/SRF axis and SMC plasticity, thus opening a new perspective for interventions of vascular pathologies.