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Interleukin-18, matrix metalloproteinase-22 and -29 are independent risk factors of human coronary heart disease

白细胞介素18、基质金属蛋白酶-22 及-29 与冠心病发生风险的关联研究

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Abstract

Background

Coronary heart disease (CHD) is characterized by arterial wall inflammation and matrix degradation. Matrix metalloproteinase (MMP)-22 and -29 and pro-inflammatory cytokine interleukin-18 (IL18) are present in human hearts. IL18 may regulate MMP-22 and -29 expression, which may correlate with CHD progression.

Methods and results

Immunoblot analysis showed that IL18 induced MMP-22 expression in human aortic smooth muscle cells. The Mann Whitney test from a prospective study of 194 CHD patients and 68 non-CHD controls demonstrated higher plasma levels of IL18, MMP-22 and -29 in CHD patients than in the controls. A logistic regression test suggested that plasma IL18 (odds ratio (OR)=1.131, P=0.007), MMP-22 (OR=1.213, P=0.040), and MMP-29 (OR=1.198, P=0.033) were independent risk factors of CHD. Pearson’s correlation test showed that IL18 (coefficient (r)=0.214, P=0.045; r=0.246, P=0.031) and MMP-22 (r=0.273, P=0.006; r=0.286, P=0.012) were associated with the Gensini score before and after adjusting for potential confounding factors. The multivariate Pearson’s correlation test showed that plasma MMP-22 levels correlated positively with high-sensitive-C-reactive protein (hs-CRP) (r=0.167, P=0.023), and MMP-29 levels correlated negatively with triglyceride (r=−0.169, P=0.018). Spearman’s correlation test indicated that plasma IL18 levels associated positively with plasma MMP-22 (r=0.845, P<0.001) and MMP-29 (r=0.548, P<0.001).

Conclusions

Our observations suggest that IL18, MMP-22 and -29 serve as biomarkers and independent risk factors of CHD. Increased systemic IL18 in CHD patients may contribute to elevated plasma MMP-22 and -29 levels in these patients.

摘要

目 的

探讨冠心病患者血浆白细胞介素18(IL18)水平是否与基质金属蛋白酶-22 和-29(MMP-22 和MMP-29)的表达水平相关, 以及此类患者血浆中MMP-22 及MMP-29 水平是否升高。

创新点

首次证实在动脉粥样硬化过程中炎症反应可能促进MMP-22 及MMP-29 的表达, IL18 是冠心病患者中调控MMP 表达的炎症因子之一。

方 法

通过免疫印迹分析检测IL18 对人体动脉平滑肌细胞MMP-22 的表达; 通过Mann Whitney 检验对来自于194 例冠心病患者和68 例对照组的前瞻性研究进行分析; 通过logistic 回归分析冠心病的独立风险因素; 通过Pearson 相关性分析IL18 和MMP-22 的表达水平与冠状动脉Gensini 积分的相关性; 通过多变量Pearson 相关性分析血浆MMP-22 水平与超敏C 反应蛋白(hs-CRP)及甘油三酯水平的相关性; 通过Spearman 相关性分析血浆IL18 水平与MMP-22 和MMP-29 的相关性。

结 论

冠心病患者血浆IL18 水平升高可能导致此类患者血浆MMP-22和MMP-29水平升高。IL18、MMP-22和MMP-29 可能是冠心病的生物标记物和独立风险因素。

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References

  • Abraham, M., Shapiro, S., Lahat, N., et al., 2002. The role of IL-18 and IL-12 in the modulation of matrix metalloproteinases and their tissue inhibitors in monocytic cells. Int. Immunol., 14(12): 1449–1457. http://dx.doi.org/10.1093/intimm/dxf108

    Article  CAS  PubMed  Google Scholar 

  • Anderson, J.L., Adams, C.D., Antman, E.M., et al., 2013. 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol., 61(23): e179–e347. http://dx.doi.org/10.1016/j.jacc.2013.01.014

    Article  PubMed  Google Scholar 

  • Arbab-Zadeh, A., Fuster, V., 2015. The myth of the “vulnerable plaque”: transitioning from a focus on individual lesions to atherosclerotic disease burden for coronary artery disease risk assessment. J. Am. Coll. Cardiol., 65(8): 846–855. http://dx.doi.org/10.1016/j.jacc.2014.11.041

    Article  PubMed  PubMed Central  Google Scholar 

  • Blankenberg, S., Tiret, L., Bickel, C., et al., 2002. Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation, 106(1): 24–30. http://dx.doi.org/10.1161/01.CIR.0000020546.30940.92

    Article  CAS  PubMed  Google Scholar 

  • Blankenberg, S., Luc, G., Ducimetiere, P., et al., 2003. Interleukin-18 and the risk of coronary heart disease in European men: the prospective epidemiological study of myocardial infarction (PRIME). Circulation, 108(20): 2453–2459. http://dx.doi.org/10.1161/01.CIR.0000099509.76044.A2

    Article  CAS  PubMed  Google Scholar 

  • Chalikias, G.K., Tziakas, D.N., Kaski, J.C., et al., 2005. Interleukin-18:interleukin-10 ratio and in-hospital adverse events in patients with acute coronary syndrome. Atherosclerosis, 182(1): 135–143. http://dx.doi.org/10.1016/j.atherosclerosis.2005.02.002

    Article  CAS  PubMed  Google Scholar 

  • Cheng, C., Tempel, D., van Haperen, R., et al., 2006. Atherosclerotic lesion size and vulnerability are determined by patterns of fluid shear stress. Circulation, 113(23): 2744–2753. http://dx.doi.org/10.1161/CIRCULATIONAHA.105.590018

    Article  PubMed  Google Scholar 

  • Creemers, E.E., Cleutjens, J.P., Smits, J.F., et al., 2001. Matrix metalloproteinase inhibition after myocardial infarction: a new approach to prevent heart failure? Circ. Res., 89(3): 201–210. http://dx.doi.org/10.1161/hh1501.094396

    Article  CAS  PubMed  Google Scholar 

  • Elhage, R., Jawien, J., Rudling, M., et al., 2003. Reduced atherosclerosis in interleukin-18 deficient apolipoprotein E-knockout mice. Cardiovasc. Res., 59(1): 234–240. http://dx.doi.org/10.1016/S0008-6363(03)00343-2

    Article  CAS  PubMed  Google Scholar 

  • Evans, J., Collins, M., Jennings, C., et al., 2007. The association of interleukin-18 genotype and serum levels with metabolic risk factors for cardiovascular disease. Eur. J. Endocrinol., 157(5): 633–640. http://dx.doi.org/10.1530/EJE-07-0463

    Article  CAS  PubMed  Google Scholar 

  • Finn, A.V., Nakano, M., Narula, J., et al., 2010. Concept of vulnerable/unstable plaque. Arterioscler. Thromb. Vasc. Biol., 30(7): 1282–1292. http://dx.doi.org/10.1161/ATVBAHA.108.179739

    Article  CAS  PubMed  Google Scholar 

  • Gensini, G.G., 1983. A more meaningful scoring system for determining the severity of coronary heart disease. Am. J. Cardiol., 51(3): 606. http://dx.doi.org/10.1016/S0002-9149(83)80105-2

    Article  CAS  PubMed  Google Scholar 

  • Gerdes, N., Sukhova, G.K., Libby, P., et al., 2002. Expression of interleukin (IL)-18 and functional IL-18 receptor on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for atherogenesis. J. Exp. Med., 195(2): 245–257. http://dx.doi.org/10.1084/jem.20011022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goncalves, I., Bengtsson, E., Colhoun, H.M., et al., 2015. Elevated plasma levels of MMP-12 are associated with atherosclerotic burden and symptomatic cardiovascular disease in subjects with type 2 diabetes. Arterioscler. Thromb. Vasc. Biol., 35(7): 1723–1731. http://dx.doi.org/10.1161/ATVBAHA.115.305631

    Article  CAS  PubMed  Google Scholar 

  • Gururajan, R., Grenet, J., Lahti, J.M., et al., 1998. Isolation and characterization of two novel metalloproteinase genes linked to the Cdc2L locus on human chromosome 1p36.3. Genomics, 52(1): 101–106. http://dx.doi.org/10.1006/geno.1998.5401

    Article  CAS  PubMed  Google Scholar 

  • Hansson, G.K., 2005. Inflammation, atherosclerosis, and coronary artery disease. N. Engl. J. Med., 352(16): 1685–1695. http://dx.doi.org/10.1056/NEJMra043430

    Article  CAS  PubMed  Google Scholar 

  • Herman, M.P., Sukhova, G.K., Libby, P., et al., 2001. Expression of neutrophil collagenase (matrix metalloproteinase-8) in human atheroma: a novel collagenolytic pathway suggested by transcriptional profiling. Circulation, 104(16): 1899–1904. http://dx.doi.org/10.1161/hc4101.097419

    Article  CAS  PubMed  Google Scholar 

  • Hu, J.H., Touch, P., Zhang, J., et al., 2015. Reduction of mouse atherosclerosis by urokinase inhibition or with a limitedspectrum matrix metalloproteinase inhibitor. Cardiovasc. Res., 105(3): 372–382. http://dx.doi.org/10.1093/cvr/cvv007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ishida, Y., Migita, K., Izumi, Y., et al., 2004. The role of IL-18 in the modulation of matrix metalloproteinases and migration of human natural killer (NK) cells. FEBS Lett., 569(1–3): 156–160. http://dx.doi.org/10.1016/j.febslet.2004.05.039

    Article  CAS  PubMed  Google Scholar 

  • Jefferis, B.J., Papacosta, O., Owen, C.G., et al., 2011. Interleukin 18 and coronary heart disease: prospective study and systematic review. Atherosclerosis, 217(1): 227–233. http://dx.doi.org/10.1016/j.atherosclerosis.2011.03.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jefferis, B.J., Whincup, P.H., Welsh, P., et al., 2013. Prospective study of IL-18 and risk of MI and stroke in men and women aged 60–79 years: a nested case-control study. Cytokine, 61(2): 513–520. http://dx.doi.org/10.1016/j.cyto.2012.10.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson, J.L., Devel, L., Czarny, B., et al., 2011. A selective matrix metalloproteinase-12 inhibitor retards atherosclerotic plaque development in apolipoprotein E-knockout mice. Arterioscler. Thromb. Vasc. Biol., 31(3): 528–535. http://dx.doi.org/10.1161/ATVBAHA.110.219147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Katsuda, S., Kaji, T., 2003. Atherosclerosis and extracellular matrix. J. Atheroscler. Thromb., 10(5): 267–274. http://dx.doi.org/10.5551/jat.10.267

    Article  CAS  PubMed  Google Scholar 

  • Kuzuya, M., Nakamura, K., Sasaki, T., et al., 2006. Effect of MMP-2 deficiency on atherosclerotic lesion formation in apoE-deficient mice. Arterioscler. Thromb. Vasc. Biol., 26(5): 1120–1125. http://dx.doi.org/10.1161/01.ATV.0000218496.60097.e0

    Article  CAS  PubMed  Google Scholar 

  • Lehrke, M., Greif, M., Broedl, U.C., et al., 2009. MMP-1 serum levels predict coronary atherosclerosis in humans. Cardiovasc. Diabetol., 8: 50. http://dx.doi.org/10.1186/1475-2840-8-50

    Article  PubMed  PubMed Central  Google Scholar 

  • Libby, P., Ridker, P.M., Hansson, G.K., et al., 2009. Inflammation in atherosclerosis: from pathophysiology to practice. J. Am. Coll. Cardiol., 54(23): 2129–2138. http://dx.doi.org/10.1016/j.jacc.2009.09.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Loftus, I.M., Naylor, A.R., Bell, P.R., et al., 2001. Plasma MMP-9—a marker of carotid plaque instability. Eur. J. Vasc. Endovasc. Surg., 21(1): 17–21. http://dx.doi.org/10.1053/ejvs.2000.1278

    Article  CAS  PubMed  Google Scholar 

  • Luttun, A., Lutgens, E., Manderveld, A., et al., 2004. Loss of matrix metalloproteinase-9 or matrix metalloproteinase-12 protects apolipoprotein E-deficient mice against atherosclerotic media destruction but differentially affects plaque growth. Circulation, 109(11): 1408–1414. http://dx.doi.org/10.1161/01.CIR.0000121728.14930.DE

    Article  CAS  PubMed  Google Scholar 

  • Ma, Y., Yabluchanskiy, A., Hall, M.E., et al., 2014. Using plasma matrix metalloproteinase-9 and monocyte chemoattractant protein-1 to predict future cardiovascular events in subjects with carotid atherosclerosis. Atherosclerosis, 232(1): 231–233. http://dx.doi.org/10.1016/j.atherosclerosis.2013.09.013

    Article  CAS  PubMed  Google Scholar 

  • Mallat, Z., Corbaz, A., Scoazec, A., et al., 2001. Expression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability. Circulation, 104(14): 1598–1603. http://dx.doi.org/10.1161/hc3901.096721

    Article  CAS  PubMed  Google Scholar 

  • Mallat, Z., Heymes, C., Corbaz, A., et al., 2004. Evidence for altered interleukin (IL)-18 pathway in human heart failure. FASEB J., 18(14): 1752–1754. http://dx.doi.org/10.1096/fj.04-2426fje

    CAS  PubMed  Google Scholar 

  • Newby, A.C., 2005. Dual role of matrix metalloproteinases (matrixins) in in timal thickening and atherosclerotic plaque rupture. Physiol. Rev., 85(1): 1–31. http://dx.doi.org/10.1152/physrev.00048.2003

    Article  CAS  PubMed  Google Scholar 

  • Nilsson, L., Jonasson, L., Nijm, J., et al., 2006. Increased plasma concentration of matrix metalloproteinase-7 in patients with coronary artery disease. Clin. Chem., 52(8): 1522–1527. http://dx.doi.org/10.1373/clinchem.2006.067439

    Article  CAS  PubMed  Google Scholar 

  • Pagidipati, N.J., Gaziano, T.A., 2013. Estimating deaths from cardiovascular disease: a review of global methodologies of mortality measurement. Circulation, 127(6): 749–756. http://dx.doi.org/10.1161/circulationaha.112.128413

    Article  PubMed  PubMed Central  Google Scholar 

  • Quiding-Jarbrink, M., Smith, D.A., Bancroft, G.J., 2001. Production of matrix metalloproteinases in response to mycobacterial infection. Infect. Immun., 69(9): 5661–5670. http://dx.doi.org/10.1128/IAI.69.9.5661-5670.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reddy, V.S., Prabhu, S.D., Mummidi, S., et al., 2010. Interleukin-18 induces EMMPRIN expression in primary cardiomyocytes via JNK/Sp1 signaling and MMP-9 in part via EMMPRIN and through AP-1 and NF-κB activation. Am. J. Physiol. Heart Circ. Physiol., 299(4): H1242–H1254. http://dx.doi.org/10.1152/ajpheart.00451.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ross, R., 1999. Atherosclerosis—an inflammatory disease. N. Engl. J. Med., 340(2): 115–126. http://dx.doi.org/10.1056/NEJM199901143400207

    Article  CAS  PubMed  Google Scholar 

  • Siasos, G., Tousoulis, D., Kioufis, S., et al., 2012. Inflammatory mechanisms in atherosclerosis: the impact of matrix metalloproteinases. Curr. Top Med. Chem., 12(10): 1132–1148. http://dx.doi.org/10.2174/1568026611208011132

    Article  CAS  PubMed  Google Scholar 

  • Task Force, M., Montalescot, G., Sechtem, U., et al., 2013. 2013 ESC guidelines on the management of stable coronary artery disease: the task force on the management of stable coronary artery disease of the European Society of Cardiology. Eur. Heart J., 34(38): 2949–3003. http://dx.doi.org/10.1093/eurheartj/eht296

    Article  Google Scholar 

  • Tenger, C., Sundborger, A., Jawien, J., et al., 2005. IL-18 accelerates atherosclerosis accompanied by elevation of IFN-γ and CXCL16 expression independently of T cells. Arterioscler. Thromb. Vasc. Biol., 25(4): 791–796. http://dx.doi.org/10.1161/01.ATV.0000153516.02782.65

    Article  CAS  PubMed  Google Scholar 

  • Thygesen, K., Alpert, J.S., Jaffe, A.S., et al., 2012. Third universal definition of myocardial infarction. J. Am. Coll. Cardiol., 60(16): 1581–1598. http://dx.doi.org/10.1016/j.jacc.2012.08.001

    Article  PubMed  Google Scholar 

  • Wang, J., Sun, C., Gerdes, N., et al., 2015. Interleukin 18 function in atherosclerosis is mediated by the interleukin 18 receptor and the Na-Cl co-transporter. Nat. Med., 21(7): 820–826. http://dx.doi.org/10.1038/nm.3890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu, S., Chen, J., Feder, J., et al., 2007. Metalloprotease Highly Expressed in the Testis, MMP-29. US Patent 7285633.

    Google Scholar 

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  1. The two authors contributed equally to this work

Authors and Affiliations

  1. Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

    Dong-Yi Jin, Cong-Lin Liu, Jun-Nan Tang, Xue-Xi Xuan, Xiao-Dan Zhu, Yun-Zhe Wang, De-Liang Shen, Xiao-Fang Wang, Guo-Ping Shi & Jin-Ying Zhang

  2. Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, 02115, USA

    Cong-Lin Liu & Guo-Ping Shi

  3. Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, 27695, USA

    Jun-Nan Tang

  4. Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA

    Zhao-Zhong Zhu

  5. Department of Biology, Pennsylvania State University, University Park, PA, 16802, USA

    Tian-Xia Zhang

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  1. Dong-Yi Jin
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Correspondence to Guo-Ping Shi or Jin-Ying Zhang.

Additional information

Project supported by the University of Science and Technology Innovation Team of Henan (No. 14IRTSTHN018), the Science and Technology Talents Team Construction Program of Zhengzhou City-Science and Technology Talents (No. 131PLJRC670), China, and the National Institutes of Health (Nos. HL60942 and HL123568), USA

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Jin, DY., Liu, CL., Tang, JN. et al. Interleukin-18, matrix metalloproteinase-22 and -29 are independent risk factors of human coronary heart disease. J. Zhejiang Univ. Sci. B 18, 685–695 (2017). https://doi.org/10.1631/jzus.B1700073

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