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Semin Neurol 2006; 26(1): 065-074
DOI: 10.1055/s-2006-933310
Published 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Vascular Biology: Cellular and Molecular Profiling

Alison E. Baird1 , Violet L. Wright1
  • 1Stroke Neuroscience Unit, NINDS/NIH, Bethesda, Maryland
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Publication History

Publication Date:
15 February 2006 (online)

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ABSTRACT

Our understanding of the mechanisms underlying cerebrovascular atherosclerosis has improved in recent years, but significant gaps remain. New insights into the vascular biological processes that result in ischemic stroke may come from cellular and molecular profiling studies of the peripheral blood. In recent cellular profiling studies, increased levels of a proinflammatory T-cell subset (CD4+CD28-) have been associated with stroke recurrence and death. Expansion of this T-cell subset may occur after ischemic stroke and be a pathogenic mechanism leading to recurrent stroke and death. Increases in certain phenotypes of endothelial cell microparticles have been found in stroke patients relative to controls, possibly indicating a state of increased vascular risk. Molecular profiling approaches include gene expression profiling and proteomic methods that permit large-scale analyses of the transcriptome and the proteome, respectively. Ultimately panels of genes and proteins may be identified that are predictive of stroke risk. Cellular and molecular profiling studies of the peripheral blood and of atherosclerotic plaques may also pave the way for the development of therapeutic agents for primary and secondary stroke prevention.

KEYWORDS

Endothelium - peripheral blood - lymphocyte - gene expression

REFERENCES

  • 1 Corti R, Fuster V. New understanding, diagnosis, and prognosis of atherothrombosis and the role of imaging.  Am J Cardiol. 2003;  91(suppl) 17A-26A
    PubMedGoogle Scholar
  • 2 Hirsch A T, Folsom A R. The continuum of risk. Vascular pathophysiology, function and structure.  Circulation. 2004;  110 2774-2777
    CrossrefPubMedGoogle Scholar
  • 3 Hallenbeck J M, Dutka A J. Background review and current concepts of reperfusion injury.  Arch Neurol. 1990;  47 1245-1254
    PubMedGoogle Scholar
  • 4 Libby P. Inflammation in atherosclerosis.  Nature. 2002;  420 868-874
    CrossrefPubMedGoogle Scholar
  • 5 DeGraba T J. Immunogenetic susceptibility of atherosclerotic stroke. Implications on current and future treatment of vascular inflammation.  Stroke. 2004;  35(suppl 1) 2712-2719
    CrossrefPubMedGoogle Scholar
  • 6 Rost N S, Wolf P A, Kase C S et al.. Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham study.  Stroke. 2001;  32 2575-2579
    CrossrefPubMedGoogle Scholar
  • 7 Curb J D, Abbott R D, Rodriguez B L et al.. C-reactive protein and the future risk of thromboembolic stroke in healthy men.  Circulation. 2003;  107 2016-2020
    CrossrefPubMedGoogle Scholar
  • 8 Toole J F, Malinow M R, Chambless L E et al.. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial.  JAMA. 2004;  291 565-575
    CrossrefPubMedGoogle Scholar
  • 9 Tanne D, Haim M, Boyko V et al.. Soluble intercellular adhesion molecule-1 and risk of future ischemic stroke: a nested case-control study from the Bezafibrate Infarction Prevention (BIP) study cohort.  Stroke. 2002;  33 2182-2186
    CrossrefPubMedGoogle Scholar
  • 10 van Exel E, Gussekloo J, de Craen AJM<, Bootsma-van der Wiel A, Frölich M, Westendorp RGJ<. Inflammation and stroke: the Leiden 85-plus study.  Stroke. 2002;  33 1135-1138
    CrossrefPubMedGoogle Scholar
  • 11 Davies P F. Molecular phenotypes of atherosclerosis. Fingering the perpetrators.  Arterioscler Thromb Vasc Biol. 2004;  24 1746-1747
    PubMedGoogle Scholar
  • 12 Ridker P M, Cannon C P, Morrow D et al.. Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) Investigators. C-reactive protein levels and outcomes after statin therapy.  N Engl J Med. 2005;  352 20-28
    CrossrefPubMedGoogle Scholar
  • 13 DeGraba T J, Sirén A-L<, Penix L et al.. Increased endothelial expression of intercellular adhesion molecule-1 (ICAM-1) in symptomatic vs asymptomatic carotid atherosclerotic plaque.  Stroke. 1998;  29 1405-1410
    PubMedGoogle Scholar
  • 14 Nadareishvili Z G, Ruetzler C, Szekely B, LaBiche R, DeGraba T J. CD4-CD154 receptor ligand interaction in Chlamydia pneumoniae positive atherosclerotic plaque.  Neurology. 2001;  56 A462
    PubMedGoogle Scholar
  • 15 Kochanek P M, Hallenbeck J M. Polymorphonuclear leukocytes and monocytes/macrophages in the pathogenesis of cerebral ischemia and stroke.  Stroke. 1992;  23 1367-1379
    PubMedGoogle Scholar
  • 16 Ernst E, Hammerschmidt D E, Bagge U, Matrai A, Dormandy J A. Leukocytes and the risk of ischemic diseases.  JAMA. 1987;  257 2318-2324
    CrossrefPubMedGoogle Scholar
  • 17 Grau A J, Boddy A W, Dukovic D A et al.. CAPRIE Investigators. Leukocyte count as an independent predictor of recurrent ischemic events.  Stroke. 2004;  35 1147-1152
    CrossrefPubMedGoogle Scholar
  • 18 Chapman C M, Beilby J P, McQuillan B M, Thompson P L, Hung J. Monocyte count, but not C-reactive protein or interleukin-6, is an independent risk marker for subclinical carotid atherosclerosis.  Stroke. 2004;  35 1619-1624
    CrossrefPubMedGoogle Scholar
  • 19 Garlichs C D, Kozina S, Fateh-Moghadam S et al.. Upregulation of CD40-CD40 ligand (CD154) in patients with acute cerebral ischemia.  Stroke. 2003;  34 1412-1418
    CrossrefPubMedGoogle Scholar
  • 20 Chen W, Wahl S M. TGF-beta: the missing link in CD4(+)CD25(+) regulatory T cell-mediated immunosuppression.  Cytokine Growth Factor Rev. 2003;  14 85-89
    CrossrefPubMedGoogle Scholar
  • 21 Becker K J. Targeting the central nervous system inflammatory response in ischemic stroke.  Curr Opin Neurol. 2001;  14 349-353
    CrossrefPubMedGoogle Scholar
  • 22 Alvord Jr E C, Hsu P C, Thron R. Leuokocyte sensitivity to brain fractions in neurological diseases.  Arch Neurol. 1974;  30 296-299
    PubMedGoogle Scholar
  • 23 Youngchaiyud U, Coates A S, Whittingham S, Mackay I R. Cellular immune response to myelin protein: absence in multiple sclerosis and presence in cerebrovascular accidents.  Aust N Z J Med. 1974;  4 535-538
    PubMedGoogle Scholar
  • 24 Wang W Z, Olsson T, Kostulas V, Hojeberg B, Ekre H P, Link H. Myelin antigen reactive T cells in cerebrovascular diseases.  Clin Exp Immunol. 1992;  88 157-162
    PubMedGoogle Scholar
  • 25 Namekawa T, Wagner U G, Goronzy J J, Weyand C M. Functional subsets of CD4 T cells in rheumatoid synovitis.  Arthritis Rheum. 1998;  41 2108-2116
    CrossrefPubMedGoogle Scholar
  • 26 Liuzzo G, Kopecky S L, Frye R L et al.. Perturbation of the T-cell repertoire in patients with unstable angina.  Circulation. 1999;  100 2135-2139
    PubMedGoogle Scholar
  • 27 Weyand C M, Gorozny J J, Liuzzo G et al.. T-cell immunity in acute coronary and syndromes.  Mayo Clin Proc. 2001;  76 1011-1020
    PubMedGoogle Scholar
  • 28 Edmead C E, Lamb J R, Hoyne G F. The T cell surface protein, CD28.  Int J Biochem Cell Biol. 1997;  29 1053-1057
    CrossrefPubMedGoogle Scholar
  • 29 Nakajima T, Schulte S, Warrington K J et al.. T-cell-mediated lysis of endothelial cells in acute coronary syndromes.  Circulation. 2002;  105 570-575
    CrossrefPubMedGoogle Scholar
  • 30 Vallejo A N, Schirmer M, Weyand C M, Goronzy J J. Clonality and longevity of CD4 + CD28null T cells are associated with defects in apoptotic pathways.  J Immunol. 2000;  165 6301-6307
    PubMedGoogle Scholar
  • 31 Nadareishvili Z, Li H, Wright V et al.. Elevated pro-inflammatory CD4+CD28- lymphocytes and stroke recurrence and death.  Neurology. 2004;  63 1446-1451
    PubMedGoogle Scholar
  • 32 Gerli R, Schillaci G, Giordano A et al.. CD4+CD28- T lymphocytes contribute to early atherosclerotic damage in rheumatoid arthritis patients.  Circulation. 2004;  109 2744-2748
    CrossrefPubMedGoogle Scholar
  • 33 Ostrowski S R, Gerstoft J, Pedersen B K, Ullum H. A low level of CD4+CD28+ T cells is an independent predictor of high mortality in human immunodeficiency virus type 1-infected patients.  J Infect Dis. 2003;  187 1726-1734
    CrossrefPubMedGoogle Scholar
  • 34 Alberts-Grill N M, Nadareishvili Z, Stranix J T et al.. Delayed expansion of pro-inflammatory CD3+CD4+CD28- lymphocytes following ischemic stroke.  Stroke. 2005;  36 517 , (Abstract)
    PubMedGoogle Scholar
  • 35 North American Symptomatic Carotid Endarterectomy Trial Collaborators . Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis.  N Engl J Med. 1991;  325 445-453
    CrossrefPubMedGoogle Scholar
  • 36 Toole J F. on behalf of the ACAS Executive Committee . ACAS recommendations for carotid endarterectomy.  Lancet. 1996;  347 121
    PubMedGoogle Scholar
  • 37 Combes V, Simon A C, Grau G E et al.. In vitro generation of endothelial microparticles and possible prothrombotic activity in patients with lupus anticoagulant.  J Clin Invest. 1999;  104 93-102
    CrossrefPubMedGoogle Scholar
  • 38 Berckmans R J, Neiuwland R, Boing A N, Romijn F P, Hack C E, Sturk A. Cell-derived microparticles circulate in healthy humans and support low grade thrombin generation.  Thromb Haemost. 2001;  85 639-646
    PubMedGoogle Scholar
  • 39 Simak J, Gelderman M, Yu H, Wright V, Alberts-Grill N, Baird A E. Elevated circulating endothelial microparticles in acute stroke patients: a correlation with brain lesion volume and clinical outcome.  Blood. 2004;  104 3504 , (Abstract)
    PubMedGoogle Scholar
  • 40 Gretarsdottir S, Thorleifsson G, Reynisdottir S T et al.. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke.  Nat Genet. 2003;  35 131-138
    PubMedGoogle Scholar
  • 41 Helgadottir A, Manolescu A, Thorleifsson G et al.. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke.  Nat Genet. 2004;  36 233-239
    PubMedGoogle Scholar
  • 42 Schena M, Shalon D, Davis R W, Brown P O. Quantitative monitoring of gene expression patterns with a complementary DNA microarray.  Science. 1995;  270 467-470
    PubMedGoogle Scholar
  • 43 Lockhart D J, Dong H, Byrne M C et al.. Expression monitoring by hybridization to high-density oligonucleotide arrays.  Nat Biotechnol. 1996;  14 1675-1680
    PubMedGoogle Scholar
  • 44 Virtanen C, Ishikawa Y, Honjoh D et al.. Integrated classification of lung tumors and cell lines by expression profiling.  Proc Natl Acad Sci USA. 2002;  99 12357-12362
    CrossrefPubMedGoogle Scholar
  • 45 Alizadeh A A, Eisen M B, Davis R E et al.. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling.  Nature. 2000;  403 503-511
    CrossrefPubMedGoogle Scholar
  • 46 Bittner M, Meltzer P, Chen Y et al.. Molecular classification of cutaneous malignant melanoma by gene expression profiling.  Nature. 2000;  406 536-540
    CrossrefPubMedGoogle Scholar
  • 47 Bhattacharjee A, Richards W G, Staunton J et al.. Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses.  Proc Natl Acad Sci USA. 2001;  98 13790-13795
    CrossrefPubMedGoogle Scholar
  • 48 Van de Vijver M J, He Y D, van't Veer L J et al.. A gene expression signature as a predictor of survival in breast cancer.  N Engl J Med. 2002;  347 1999-2009
    CrossrefPubMedGoogle Scholar
  • 49 Jones M H, Virtanen C, Honjoh D et al.. Two prognostically significant subtypes of high-grade lung neuroendocrine tumors independent of small-cell and large-cell neuroendocrine carcinomas identified by gene expression profiles.  Lancet. 2004;  363 775-781
    CrossrefPubMedGoogle Scholar
  • 50 Chang J C, Wooten E C, Tsimelzon A et al.. Gene expression profiling for the prediction of therapeutic response to docetaxel in patients with breast cancer.  Lancet. 2003;  362 362-369
    CrossrefPubMedGoogle Scholar
  • 51 Barrans J D, Allen P D, Stamatiou D, Dzau V J, Liew C C. Global gene expression profiling of end-stage dilated cardiomyopathy using a human cardiovascular-based cDNA microarray.  Am J Pathol. 2002;  160 2035-2043
    PubMedGoogle Scholar
  • 52 Moore D F, Li H, Jeffries N et al.. Using peripheral blood mononuclear cells to determine a gene expression profile of acute ischemic stroke: a pilot investigation.  Circulation. 2005;  111 212-221
    CrossrefPubMedGoogle Scholar
  • 53 Jison M L, Munson P J, Barb J J et al.. Blood mononuclear cell gene expression profiles characterize the oxidant, hemolytic and inflammatory stress of sickle cell disease.  Blood. 2004;  104 270-280
    CrossrefPubMedGoogle Scholar
  • 54 Seo D, Wang T, Dressman H et al.. Gene expression phenotypes of atherosclerosis.  Arterioscler Thromb Vasc Biol. 2004;  24 1922-1927
    CrossrefPubMedGoogle Scholar
  • 55 Greenberg S A. DNA microarray gene expression analysis and its application to neurological disorders.  Neurology. 2001;  57 755-761
    PubMedGoogle Scholar
  • 56 Napoli C, Lerman L O, Sica V, Lerman A, Tajana G, de Nigris F. Microarray analysis: a novel research tool for cardiovascular scientists and physicians.  Heart. 2003;  89 597-604
    CrossrefPubMedGoogle Scholar
  • 57 Collins F S, Green E D, Guttmacher A E, Guyer M S. on behalf of the US National Human Genome Research Institute . A vision for the future of genomics research.  Nature. 2003;  422 835-847
    CrossrefPubMedGoogle Scholar
  • 58 Anderson L. Candidate-based proteomics in the search for biomarkers of cardiovascular disease.  J Physiol. 2005;  563 23-60
    PubMedGoogle Scholar
  • 59 Allard L, Lescuyer P, Burgess J et al.. ApoC-I and ApoC-III as potential plasmatic markers to distinguish between ischemic and hemorrhagic stroke.  Proteomics. 2004;  4 2242-2251
    CrossrefPubMedGoogle Scholar
  • 60 Lynch J R, Blessing R, White W D, Grocott H P, Newman M F, Laskowitz D T. Novel diagnostic test for acute stroke.  Stroke. 2004;  35 57-63
    PubMedGoogle Scholar

Alison E BairdF.R.A.C.P. Ph.D. 

Stroke Neuroscience Unit, NINDS/NIH, 10 Center Drive, MSC1294, Room 3N258, Bethesda, MD 20814

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