Vascular Biology: Cellular and Molecular Profiling

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.

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
• 2 Hirsch A T, Folsom A R. The continuum of risk. Vascular pathophysiology, function and structure.  Circulation. 2004;  110 2774-2777
• 3 Hallenbeck J M, Dutka A J. Background review and current concepts of reperfusion injury.  Arch Neurol. 1990;  47 1245-1254
• 4 Libby P. Inflammation in atherosclerosis.  Nature. 2002;  420 868-874
• 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
• 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
• 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
• 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
• 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
• 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
• 11 Davies P F. Molecular phenotypes of atherosclerosis. Fingering the perpetrators.  Arterioscler Thromb Vasc Biol. 2004;  24 1746-1747
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 21 Becker K J. Targeting the central nervous system inflammatory response in ischemic stroke.  Curr Opin Neurol. 2001;  14 349-353
• 22 Alvord Jr E C, Hsu P C, Thron R. Leuokocyte sensitivity to brain fractions in neurological diseases.  Arch Neurol. 1974;  30 296-299
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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)
• 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
• 36 Toole J F. on behalf of the ACAS Executive Committee . ACAS recommendations for carotid endarterectomy.  Lancet. 1996;  347 121
• 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
• 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
• 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)
• 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
• 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
• 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
• 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
• 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
• 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
• 46 Bittner M, Meltzer P, Chen Y et al.. Molecular classification of cutaneous malignant melanoma by gene expression profiling.  Nature. 2000;  406 536-540
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 54 Seo D, Wang T, Dressman H et al.. Gene expression phenotypes of atherosclerosis.  Arterioscler Thromb Vasc Biol. 2004;  24 1922-1927
• 55 Greenberg S A. DNA microarray gene expression analysis and its application to neurological disorders.  Neurology. 2001;  57 755-761
• 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
• 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
• 58 Anderson L. Candidate-based proteomics in the search for biomarkers of cardiovascular disease.  J Physiol. 2005;  563 23-60
• 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
• 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