Case Center for Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, Ohio 441061, USA.
J Biol Chem. 2012 Jul 27;287(31):25869-80. doi: 10.1074/jbc.M112.375204. Epub 2012 May 30.
Histone acetylation was significantly increased in retinas from diabetic rats, and this acetylation was inhibited in diabetics treated with minocycline, a drug known to inhibit early diabetic retinopathy in animals. Histone acetylation and expression of inflammatory proteins that have been implicated in the pathogenesis of diabetic retinopathy were increased likewise in cultured retinal Müller glia grown in a diabetes-like concentration of glucose. Both the acetylation and induction of the inflammatory proteins in elevated glucose levels were significantly inhibited by inhibitors of histone acetyltransferase (garcinol and antisense against the histone acetylase, p300) or activators of histone deacetylase (theophylline and resveratrol) and were increased by the histone deacetylase inhibitor, suberolylanilide hydroxamic acid. We conclude that hyperglycemia causes acetylation of retinal histones (and probably other proteins) and that the acetylation contributes to the hyperglycemia-induced up-regulation of proinflammatory proteins and thereby to the development of diabetic retinopathy.
组蛋白乙酰化在糖尿病大鼠的视网膜中显著增加，而米诺环素治疗的糖尿病患者的这种乙酰化受到抑制，米诺环素是一种已知可抑制动物早期糖尿病视网膜病变的药物。在类似于糖尿病的葡萄糖浓度下培养的视网膜 Müller 胶质细胞中，同样也增加了与糖尿病性视网膜病变发病机制有关的组蛋白乙酰化和炎症蛋白的表达。组蛋白乙酰转移酶抑制剂（garcinol 和针对组蛋白乙酰酶 p300 的反义寡核苷酸）或组蛋白去乙酰化酶激活剂（茶碱和白藜芦醇）显著抑制了高葡萄糖水平下的乙酰化和炎症蛋白的诱导，而组蛋白去乙酰化酶抑制剂（suberoylanilide hydroxamic acid）则增加了乙酰化和炎症蛋白的诱导。我们得出结论，高血糖导致视网膜组蛋白（和可能的其他蛋白质）乙酰化，并且这种乙酰化有助于高血糖诱导的促炎蛋白的上调，从而导致糖尿病性视网膜病变的发展。
