Genomic Profiling of Acquired Resistance to Apoptosis in Cells Derived From Human Atherosclerotic Lesions: Potential Role of STATs, cyclinD1, BAD, and Bcl-XL

J Mol Cell Cardiol. 2005 Sep;39(3):453-65. doi: 10.1016/j.yjmcc.2005.01.015.

Abstract

Current theories suggest that atherosclerosis, plaque rupture, stroke, and restenosis after angioplasty may involve defective apoptotic mechanisms in vascular cells. Prior work has demonstrated that cells from human atherosclerotic lesions, and cells from the aorta of aged rats, exhibit functional resistance to apoptosis induced by TGF-beta and glucocorticoids. The present studies demonstrate that human lesion-derived cells (LDC) are also resistant to apoptosis induced by fas ligation compared to cells derived from the adjacent media, and that in vitro expansion of LDC causes acquired resistance to apoptosis. Microarray profiling of fas-resistant versus sensitive cells identified a set of genes including STATs, caspase 1, cyclin D1, Bcl-xL, VDAC2, and BAD. The STAT proteins have been implicated in resistance to apoptosis, potentially via their ability to modulate caspase 1 (ICE), Bcl-xL, and cyclin D1 expression. Western blot analysis of sensitive and resistant LDC clonal lines confirmed increases in cyclin D1, STAT6, Bcl-xL, and BAD, with decreased expression of caspase 1. Thus, transcript profiling has identified a potential pathway of apoptotic regulation in subsets of lesion cells. The resistant phenotype may contribute to plaque stability and excessive vascular repair, while sensitive cells may be involved in plaque rupture and infarction. The data suggests both genetic interventions and novel small-molecule inhibitors that may be effective modulators of apoptosis in atherosclerosis, angina, and in-stent restenosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis / genetics*
  • Arteriosclerosis / genetics
  • Arteriosclerosis / pathology*
  • Blotting, Western
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Survival
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Gene Expression Profiling
  • Genome, Human
  • Humans
  • Models, Anatomic
  • Models, Biological
  • Oligonucleotide Array Sequence Analysis
  • Porins / genetics
  • Porins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • RNA, Messenger / genetics
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • STAT6 Transcription Factor
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Voltage-Dependent Anion Channel 2
  • Voltage-Dependent Anion Channels
  • bcl-Associated Death Protein
  • bcl-X Protein
  • fas Receptor / physiology

Substances

  • BAD protein, human
  • BCL2L1 protein, human
  • Carrier Proteins
  • DNA-Binding Proteins
  • Porins
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Messenger
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • STAT6 Transcription Factor
  • STAT6 protein, human
  • Trans-Activators
  • VDAC2 protein, human
  • Voltage-Dependent Anion Channel 2
  • Voltage-Dependent Anion Channels
  • bcl-Associated Death Protein
  • bcl-X Protein
  • fas Receptor
  • Cyclin D1