Acetylation of retinal histones in diabetes increases inflammatory proteins: effects of minocycline and manipulation of histone acetyltransferase (HAT) and histone deacetylase (HDAC).
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.
Case Center for Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, Ohio 441061, USA.
Chandra Sekhar Rao
CS
Kadiyala
Ling
L
Zheng
Yunpeng
Y
Du
Elizabeth
E
Yohannes
Hung-Ying
HY
Kao
Masaru
M
Miyagi
Timothy S
TS
Kern
D000107:Acetylation / Q000187:drug effects; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008911:Minocycline / Q000494:pharmacology* / Q000627:therapeutic use; D008969:Molecular Sequence Data; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry; D011499:Protein Processing, Post-Translational; D051381:Rats; D011917:Rats, Inbred Lew; D012160:Retina / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D013729:Terpenes / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D018836:Inflammation Mediators; D010446:Peptide Fragments; D013729:Terpenes; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D018799:Intercellular Adhesion Molecule-1; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases; D008911:Minocycline; C054597:garcinol