Effects of oxidized and glycated LDL on gene expression in human retinal capillary pericytes.
OBJECTIVE
Modified (oxidized and/or glycated) low-density lipoproteins (LDLs) have been implicated in retinal pericyte loss, one of the major pathologic features of early-stage diabetic retinopathy. To delineate underlying molecular mechanisms, the present study was designed to explore the global effects of modified LDL on pericyte gene expression.


METHODS
Quiescent human retinal pericytes were exposed to native LDL (N-LDL), glycated LDL (G-LDL), and heavily oxidized-glycated LDL (HOG-LDL) for 24 hours, and gene expression was evaluated by DNA microarray analysis. Several of the gene responses were checked, and in each case confirmed by reverse-transcription real-time PCR.


RESULTS
HOG-LDL induced a gene expression pattern markedly distinct from that of N-LDL or G-LDL, whereas G-LDL elicited gene expression similar to that of N-LDL. A comparison of responses to HOG-LDL versus N-LDL revealed 60 genes with expression that varied by > or =1.7-fold. The HOG-LDL-responsive genes included members of functional pathways, such as fatty acid, eicosanoid, and cholesterol metabolism; fibrinolytic regulation; cell growth and proliferation; cell stress responses; the kinin system; and angiogenesis.


CONCLUSIONS
HOG-LDL elicits gene expression in retinal pericytes that may contribute to pericyte loss and other retinal abnormalities in diabetic retinopathy. Observed proapoptotic and proangiogenic responses to HOG-LDL may be of particular importance in this regard. The genes identified through these studies provide potential therapeutic targets for the prevention and treatment of diabetic retinopathy.
Song
Weiwei
W
Section of Endocrinology and Diabetes, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Barth
Jeremy L
JL
Yu
Yongxin
Y
Lu
Kangmo
K
Dashti
Azar
A
Huang
Yan
Y
Gittinger
Cynthia K
CK
Argraves
W Scott
WS
Lyons
Timothy J
TJ
D000328:Adult; D002196:Capillaries; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D017127:Glycation End Products, Advanced; D006801:Humans; D008077:Lipoproteins, LDL / Q000187:drug effects* / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D020286:Pericytes / Q000187:drug effects / Q000378:metabolism*; D012171:Retinal Vessels / Q000166:cytology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000093844:Glycated Proteins
D017127:Glycation End Products, Advanced; D008077:Lipoproteins, LDL; C031797:glycated lipoproteins, LDL; D000093844:Glycated Proteins; C099252:oxidized low density lipoprotein