Large Impact of Low Concentration Oxidized LDL on Angiogenic Potential of Human Endothelial Cells: A Microarray StudyReportar como inadecuado

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Oxidized LDL ox-LDL is a key factor in atherogenesis. It is taken up by endothelial cells primarily by ox-LDL receptor-1 LOX-1. To elucidate transcriptional responses, we performed microarray analysis on human coronary artery endothelial cells HCAECs exposed to small physiologic concentration of ox-LDL- 5 µg-ml for 2 and 12 hours. At 12 hours, cultures treated with ox-LDL exhibited broad shifts in transcriptional activity involving almost 1500 genes >1.5 fold difference, p<0.05. Resulting transcriptome was enriched for genes associated with cell adhesion p<0.002, angiogenesis p<0.0002 and migration p<0.006. Quantitative PCR analysis revealed that LOX-1 expression in HCAECs is at least an order of magnitude greater than the expression of other major ox-LDL specific receptors CD36 and MSR1. In keeping with the data on LOX-1 expression, pre-treatment of HCAECs with LOX-1 neutralizing antibody resulted in across-the-board inhibition of cellular response to ox-LDL. Ox-LDL upregulated a number of pro-angiogenic genes including multiple receptors, ligands and transcription factors and altered the expression of a number of genes implicated in both stimulation and inhibition of apoptosis. From a functional standpoint, physiologic concentrations of ox-LDL stimulated tube formation and inhibited susceptibility to apoptosis in HCAECs. In addition, ox-LDL exposure resulted in upregulation of miR-1974, miR-1978 and miR-21 accompanied with significant over-presentation of their target genes in the downregulated portion of ox-LDL transcriptome. Our observations indicate that ox-LDL at physiologic concentrations induces broad transcriptional responses which are mediated by LOX-1, and are, in part, shaped by ox-LDL-dependent miRNAs. We also suggest that angiogenic effects of ox-LDL are partially based on upregulation of several receptors that render cells hypersensitive to angiogenic stimuli.

Autor: Magomed Khaidakov , Sona Mitra, Xianwei Wang, Zufeng Ding, Nalini Bora, Valery Lyzogubov, Francesco Romeo, Steven A. Schichman, J



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