Epigenetic upregulation of p66shc mediates low-density lipoprotein cholesterol-induced endothelial cell dysfunction.
Hypercholesterolemia characterized by elevation of low-density lipoprotein (LDL) cholesterol is a major risk factor for atherosclerotic vascular disease. p66shc mediates hypercholesterolemia-induced endothelial dysfunction and atheromatous plaque formation. We asked if LDL upregulates endothelial p66shc via changes in the epigenome and examined the role of p66shc in LDL-stimulated endothelial cell dysfunction. Human LDL stimulates human p66shc promoter activity and p66shc expression in human endothelial cells. LDL leads to hypomethylation of two CpG dinucleotides and acetylation of histone 3 in the human p66shc promoter. These two CpG dinucleotides mediate LDL-stimulated p66shc promoter activity. Inhibition or knock down of DNA methyltransferases negates LDL-induced endothelial p66shc expression. p66shc mediates LDL-stimulated increase in expression of endothelial intercellular adhesion molecule-1 (ICAM1) and decrease in expression of thrombomodulin (TM). Mirroring these changes in ICAM1 and TM expression, p66shc mediates LDL-stimulated adhesion of monocytes to endothelial cells and plasma coagulation on endothelial cells. These findings indicate that LDL cholesterol upregulates human endothelial p66shc expression via hypomethylation of CpG dinucleotides in the p66shc promoter. Moreover, they show that LDL-stimulated p66shc expression mediates a dysfunctional endothelial cell surface, with proadhesive and procoagulant features.
Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
Young-Rae
YR
Kim
Cuk-Seong
CS
Kim
Asma
A
Naqvi
Ajay
A
Kumar
Santosh
S
Kumar
Timothy A
TA
Hoffman
Kaikobad
K
Irani
D000107:Acetylation; D001777:Blood Coagulation / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D008078:Cholesterol, LDL / Q000494:pharmacology / Q000502:physiology*; D015254:DNA Modification Methylases / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D044127:Epigenesis, Genetic; D006657:Histones / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D009000:Monocytes / Q000502:physiology; D011401:Promoter Regions, Genetic; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D018180:Thrombomodulin / Q000096:biosynthesis; D015854:Up-Regulation
D008078:Cholesterol, LDL; D006657:Histones; C573420:ICAM1 protein, human; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D018180:Thrombomodulin; D018799:Intercellular Adhesion Molecule-1; D015254:DNA Modification Methylases