Characterization of a novel endothelial biosensor assay reveals increased cumulative serum inflammatory potential in stabilized coronary artery disease patients

Journal of Translational Medicine

Matthew J Campen⁴  Clifford Qualls³  Akshay Sood²  Carlos Roldan²  James Nawarskas¹  Joe R Anderson¹  Katherine Zychowski⁴  Mario J Aragon⁴  Heidi Cung⁴ 

[1] Department of Pharmacy Practice and Administrative Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM, USA;Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA;Department of Biostatistics, School of Medicine, University of New Mexico, Albuquerque, NM, USA;Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM, USA

关键词: Endothelial;    Serum;    Inflammatory;    Biomarker;    Coronary artery disease;   

Others  :  1146134
DOI  :  10.1186/s12967-015-0457-5

 received in 2014-12-22, accepted in 2015-03-10,  发布年份 2015

【 摘 要 】

Background

Vascular disease is promoted by systemic inflammation that can arise from sites distal to the affected vessels. We sought to characterize the net inflammatory potential of serum from patients with coronary artery disease (CAD) using cultured endothelial cells as a cumulative biosensor.

Methods and results

Serum samples from CAD patients (N = 45) and healthy control subjects (N = 48) were incubated with primary human coronary artery endothelial cells at a 1:10 dilution for 4 h, followed by isolation of the cellular RNA. Alteration of inflammation-responsive elements (adhesion molecules and cytokines) was assessed by gene expression. Specific indicators included intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and interleukin-8 (IL-8). Additionally, the cytokine levels in serum samples from all subjects were quantified. Serum from CAD subjects induced greater endothelial ICAM-1, VCAM-1, and IL-8 expression compared to healthy control serum (p < 0.001 for each analysis). The three indicators of inflammatory potential (ICAM-1, VCAM-1, and IL-8 mRNA) trended independently of each other and also of serum inflammatory biomarkers. IL-8 expression correlated negatively with serum HDL levels but positively correlated with VLDL, plasminogen activator inhibitor-1 and C-reactive protein. Interestingly, serum levels of cytokines in CAD patients were not statistically different from healthy control subjects. A year of follow-up in a sub-group of CAD subjects revealed relatively stable measures.

Conclusions

As yet unidentified circulating factors in the serum of CAD patients appear to activate endothelial cells, leading to upregulation of adhesion molecules and chemokines. This cumulative assay performed well in terms of discriminating patients with CAD compared to healthy subjects, with greater range and specificity than specific inflammatory markers.

【 授权许可】

   
2015 Cung et al.; licensee BioMed Central.

【 图 表 】

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【 参考文献 】

• [1]Ross R: Atherosclerosis–an inflammatory disease. N Engl J Med 1999, 340:115-26. doi:10.1056/NEJM199901143400207
• [2]Corbi G, Bianco A, Turchiarelli V, Cellurale M, Fatica F, Daniele A, et al.: Potential Mechanisms Linking Atherosclerosis and Increased Cardiovascular Risk in COPD: Focus On Sirtuins. Int J Mol Sci 2013, 14:12696-713. doi:10.3390/ijms140612696
• [3]Van Eeden S, Leipsic J, Paul Man SF, Sin DD: The relationship between lung inflammation and cardiovascular disease. Am J Respir Crit Care Med 2012, 186:11-6. doi:10.1164/rccm.201203-0455PP
• [4]Lahousse L, van den Bouwhuijsen QJ, Loth DW, Joos GF, Hofman A, Witteman JC, et al.: Chronic obstructive pulmonary disease and lipid core carotid artery plaques in the elderly: the Rotterdam Study. Am J Respir Crit Care Med 2013, 187:58-64. doi:10.1164/rccm.201206-1046OC
• [5]Kucukazman M, Ata N, Yavuz B, Dal K, Sen O, Deveci OS, et al.: Evaluation of early atherosclerosis markers in patients with nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol 2013, 25:147-51. doi:10.1097/MEG.0b013e32835a58b1
• [6]Brea A, Mosquera D, Martin E, Arizti A, Cordero JL, Ros E: Nonalcoholic fatty liver disease is associated with carotid atherosclerosis: a case–control study. Arterioscler Thromb Vasc Biol 2005, 25:1045-50. doi:10.1161/01.ATV.0000160613.57985.18
• [7]Barve S, Joshi-Barve S, Song Z, Hill D, Hote P, Deaciuc I, et al.: Interactions of cytokines, S-Adenosylmethionine, and S-Adenosylhomocysteine in alcohol-induced liver disease and immune suppression. J Gastroenterol Hepatol 2006, 21(Suppl 3):S38-42. doi:10.1111/j.1440-1746.2006.04590.x
• [8]McClain CJ, Hill DB, Song Z, Chawla R, Watson WH, Chen T, et al.: S-Adenosylmethionine, cytokines, and alcoholic liver disease. Alcohol 2002, 27:185-92.
• [9]Liang YJ, Shyu KG, Wang BW, Lai LP: C-reactive protein activates the nuclear factor-kappaB pathway and induces vascular cell adhesion molecule-1 expression through CD32 in human umbilical vein endothelial cells and aortic endothelial cells. J Mol Cell Cardiol 2006, 40:412-20. doi:10.1016/j.yjmcc.2005.12.008
• [10]Kawanami D, Maemura K, Takeda N, Harada T, Nojiri T, Saito T, et al.: C-reactive protein induces VCAM-1 gene expression through NF-kappaB activation in vascular endothelial cells. Atherosclerosis 2006, 185:39-46. doi:10.1016/j.atherosclerosis.2005.01.057
• [11]Montgomery KF, Osborn L, Hession C, Tizard R, Goff D, Vassallo C, et al.: Activation of endothelial-leukocyte adhesion molecule 1 (ELAM-1) gene transcription. Proc Natl Acad Sci U S A 1991, 88:6523-7.
• [12]Yousuf O, Mohanty BD, Martin SS, Joshi PH, Blaha MJ, Nasir K, et al.: High-sensitivity C-reactive protein and cardiovascular disease: a resolute belief or an elusive link? J Am Coll Cardiol 2013, 62:397-408. doi:10.1016/j.jacc.2013.05.016
• [13]Channell MM, Paffett ML, Devlin RB, Madden MC, Campen MJ: Circulating factors induce coronary endothelial cell activation following exposure to inhaled diesel exhaust and nitrogen dioxide in humans: evidence from a novel translational in vitro model. Toxicol Sci 2012, 127:179-86. doi:10.1093/toxsci/kfs084
• [14]Barua RS, Ambrose JA, Srivastava S, DeVoe MC, Eales-Reynolds LJ: Reactive oxygen species are involved in smoking-induced dysfunction of nitric oxide biosynthesis and upregulation of endothelial nitric oxide synthase: an in vitro demonstration in human coronary artery endothelial cells. Circulation 2003, 107:2342-7. doi:10.1161/01.CIR.0000066691.52789.BE
• [15]Barbieri SS, Zacchi E, Amadio P, Gianellini S, Mussoni L, Weksler BB, et al.: Cytokines present in smokers’ serum interact with smoke components to enhance endothelial dysfunction. Cardiovasc Res 2011, 90:475-83. doi:10.1093/cvr/cvr032
• [16]Agarwal B, Campen MJ, Channell MM, Wherry SJ, Varamini B, Davis JG, et al.: Resveratrol for primary prevention of atherosclerosis: clinical trial evidence for improved gene expression in vascular endothelium. Int J Cardiol 2013, 166:246-8. doi:10.1016/j.ijcard.2012.09.027
• [17]Robertson S, Colombo ES, Lucas SN, Hall PR, Febbraio M, Paffett ML, et al.: CD36 mediates endothelial dysfunction downstream of circulating factors induced by O3 exposure. Toxicol Sci 2013, 134:304-11. doi:10.1093/toxsci/kft107
• [18]Campen M, Robertson S, Lund A, Lucero J, McDonald J: Engine exhaust particulate and gas phase contributions to vascular toxicity. Inhal Toxicol 2014, 26:353-60. doi:10.3109/08958378.2014.897776
• [19]Heyward VH: Practical body composition assessment for children, adults, and older adults. Int J Sport Nutr 1998, 8:285-307.
• [20]Kaptoge S, Di Angelantonio E, Pennells L, Wood AM, White IR, et al.: Emerging Risk Factors C: C-reactive protein, fibrinogen, and cardiovascular disease prediction. N Engl J Med 2012, 367:1310-20. doi:10.1056/NEJMoa1107477
• [21]Di Angelantonio E, Gao P, Pennells L, Kaptoge S, Caslake M, et al.: Emerging Risk Factors C: Lipid-related markers and cardiovascular disease prediction. JAMA 2012, 307:2499-506. doi:10.1001/jama.2012.6571
• [22]Sever PS, Poulter NR, Chang CL, Thom SA, Hughes AD, Welsh P, et al.: Evaluation of C-reactive protein before and on-treatment as a predictor of benefit of atorvastatin: a cohort analysis from the Anglo-Scandinavian Cardiac Outcomes Trial lipid-lowering arm. J Am Coll Cardiol 2013, 62:717-29. doi:10.1016/j.jacc.2013.02.098
• [23]Pearson T, Ballantyne C, Sisk C, Shah A, Veltri E, Maccubbin D: Comparison of effects of ezetimibe/simvastatin versus simvastatin versus atorvastatin in reducing C-reactive protein and low-density lipoprotein cholesterol levels. Am J Cardiol 2007, 99:1706-13. doi:10.1016/j.amjcard.2007.01.062
• [24]Ikonomidis I, Andreotti F, Economou E, Stefanadis C, Toutouzas P, Nihoyannopoulos P: Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin. Circulation 1999, 100:793-8.
• [25]Woodward M, Lowe GD, Francis LM, Rumley A, Cobbe SM, Investigators CS: A randomized comparison of the effects of aspirin and clopidogrel on thrombotic risk factors and C-reactive protein following myocardial infarction: the CADET trial. J Thromb Haemost 2004, 2:1934-40. doi:10.1111/j.1538-7836.2004.01017.x
• [26]Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI: Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 2002, 106:679-84.
• [27]Sola S, Mir MQ, Lerakis S, Tandon N, Khan BV: Atorvastatin improves left ventricular systolic function and serum markers of inflammation in nonischemic heart failure. J Am Coll Cardiol 2006, 47:332-7. doi:10.1016/j.jacc.2005.06.088
• [28]Solheim S, Pettersen AA, Arnesen H, Seljeflot I: No difference in the effects of clopidogrel and aspirin on inflammatory markers in patients with coronary heart disease. Thromb Haemost 2006, 96:660-4.