|Title:||TPL2 (therapeutic targeting tumor progression locus-2)/ATF4 (activating transcription factor-4)/SDF1α (chemokine stromal cell-derived factor-α) axis suppresses diabetic retinopathy||Authors:||Lai D.-W.
|Keywords:||ATF4; Diabetic retinopathy; ER stress; N?-(Carboxymethyl)-L-lysine; SDF1α; TPL2; VEGF||Issue Date:||2017||Publisher:||Lippincott Williams and Wilkins||Journal Volume:||121||Journal Issue:||6||Start page/Pages:||e37-e52||Source:||Circulation Research||Abstract:||
Rationale: Diabetic retinopathy is characterized by vasopermeability, vascular leakage, inflammation, blood- retinal barrier breakdown, capillary degeneration, and neovascularization. However, the mechanisms underlying the association between diabetes mellitus and progression retinopathy remain unclear. Objective: TPL2 (tumor progression locus 2), a serine-threonine protein kinase, exerts a pathological effect on vascular angiogenesis. This study investigated the role of N?-(carboxymethyl)lysine, a major advanced glycation end products, and the involved TPL2-related molecular signals in diabetic retinopathy using models of in vitro and in vivo and human samples. Methods and Results: Serum N?-(carboxymethyl)lysine levels and TPL2 kinase activity were significantly increased in clinical patients and experimental animals with diabetic retinopathy. Intravitreal administration of pharmacological blocker or neutralizing antibody inhibited TPL2 and effectively suppressed the pathological characteristics of retinopathy in streptozotocin-induced diabetic animal models. Intravitreal VEGF (vascular endothelial growth factor) neutralization also suppressed the diabetic retinopathy in diabetic animal models. Mechanistic studies in primary human umbilical vein endothelial cells and primary retinal microvascular endothelial cells from streptozotocin-diabetic rats, db/db mice, and samples from patients with diabetic retinopathy revealed a positive parallel correlation between N?-(carboxymethyl)lysine and the TPL2/chemokine SDF1α (stromal cell-derived factor-α) axis that is dependent on endoplasmic reticulum stress-related molecules, especially ATF4 (activating transcription factor-4). Conclusions: This study demonstrates that inhibiting the N?-(carboxymethyl)lysine-induced TPL2/ATF4/SDF1α axis can effectively prevent diabetes mellitus-mediated retinal microvascular dysfunction. This signaling axis may include the therapeutic potential for other diseases involving pathological neovascularization or macular edema. ? 2017 American Heart Association, Inc.
|ISSN:||0009-7330||DOI:||10.1161/CIRCRESAHA.117.311066||SDG/Keyword:||activating transcription factor 4; advanced glycation end product; protein serine threonine kinase; stromal cell derived factor 1alpha; tumor progression locus 2 protein; unclassified drug; vasculotropin; activating transcription factor 4; lysine; mitogen activated protein kinase kinase kinase; N(6)-carboxymethyllysine; stromal cell derived factor 1; animal cell; animal experiment; animal model; Article; capillary endothelial cell; controlled study; diabetic retinopathy; endoplasmic reticulum stress; human; human cell; in vitro study; in vivo study; mouse; nonhuman; priority journal; protein protein interaction; rat; signal transduction; streptozotocin-induced diabetes mellitus; umbilical vein endothelial cell; analogs and derivatives; animal; blood; C57BL mouse; cell culture; diabetic retinopathy; experimental diabetes mellitus; metabolism; Sprague Dawley rat; Activating Transcription Factor 4; Animals; Cells, Cultured; Chemokine CXCL12; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Human Umbilical Vein Endothelial Cells; Humans; Lysine; MAP Kinase Kinase Kinases; Mice; Mice, Inbred C57BL; Rats; Rats, Sprague-Dawley; Signal Transduction
|Appears in Collections:||毒理學研究所|
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