| Prior Exposure to Oxidized Low Density Lipoprotein Limits Apoptosis in Subsequent Generations of Endothelial Cells by Altering Promoter Methylation. | |
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MedLine Citation:
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PMID: 21602467 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Oxidized LDL (ox-LDL) plays a critical role in atherogenesis, including apoptosis. As hypercholesterolemia causes epigenetic changes resulting in long-term phenotypic consequences, we hypothesized that repeated and continuous exposure to ox-LDL may alter the pattern of apoptosis in human umbilical vein endothelial cells (HUVECs). We also analyzed global and promoter-specific methylation of apoptosis-related genes. As expected, ox-LDL evoked a dose-dependent increase in apoptosis in the first passage HUVECs that was completely abrogated by LOX-1 neutralizing antibody. Ox-LDL-induced apoptosis was associated with up regulation of pro-apoptotic LOX-1, ANXA5, BAX and CASP3 and inhibition of anti- apoptotic BCL2 and cIAP-1 genes accompanied with reciprocal changes in the methylation of promoter regions of these genes. Subsequent passages of cells displayed attenuated apoptotic response to repeat ox-LDL challenge with blunted gene expression, and exaggerated methylation of LOX-1, BAX, ANXA5 and CASP3 genes (all P<0.05 vs. 1st Exposure to ox-LDL). Treatment of cells with LOX-1 antibody prior to initial ox-LDL treatment prevented both gene-specific promoter methylation and expression changes and reduction of apoptotic response to repeat ox-LDL challenge. Based on these data, we conclude that exposure of HUVECs to ox-LDL induces epigenetic changes leading to resistance to apoptosis in subsequent generations, and this effect may be related to LOX-1 mediated increase in DNA methylation. |
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Authors:
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Sona Mitra; Magomed Khaidakov; Jingjun Lu; Srinivas Ayyadevara; Jackob Szwedo; Xian Wei Wang; Chien Chen; Srikanth Reddy Kasula; Annjanette Stone; Igor Pogribny; Jawahar L Mehta |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-5-20 |
Journal Detail:
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Title: American journal of physiology. Heart and circulatory physiology Volume: - ISSN: 1522-1539 ISO Abbreviation: - Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-5-23 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100901228 Medline TA: Am J Physiol Heart Circ Physiol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1. |
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