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Article*
"Development of the European Network in Orphan Cardiovascular Diseases"
„Rozszerzenie Europejskiej Sieci Współpracy ds Sierocych Chorób Kardiologicznych”
Title: Chemokine RANTES and it’s role in endothelial
dysfunction and severity of atherosclerosis
Author: Jakub Podolec MD, PhD
Affiliation: Department of Hemodynamics and Angiocardiography, Cardiology Institute,
Collegium Medicum, Jagiellonian University at the John Paul II Hospital, Krakow, Poland
Date: 29.11.2013
Background
Heart diseases are the leading cause of death in Europe and it represents around 50%
of overall mortality. Cardiovascular heart diseases are the most common diagnosis made after
patient discharge (2557/100000 people/year) [1]. It is of great importance to evaluate patients
at high CAD risk. New risk markers including: homocysteine, inflammatory molecules (ex.
CRP, interleukines), vWF, fibrynogen, IMT and calcium score are widely proven to predict
adverse cardiovascular events [2,3]. Still many cardiac markers are under investigation with
an aim to evaluate patients to different risk groups and predict more adequate cardio-cerebral
events.
Literature Review
Cytokines play an important role in the process of leukocyte activation and migration
to the inflammation spot. Chemokines as a class of chemotactic cytokines is believed to be
involved in atherosclerotic plaque formation. It was proven that some of the chemokines such
as CCL3/MIP1a, CCL5/ RANTES, and CCL18/PARC are expressed in atherosclerosis
[4,5,6]. Among CCL5/RANTES receptors one may indicate specific ones such as: CCR5,
John Paul II Hospital in Kraków
Jagiellonian University, Institute of Cardiology
80 Prądnicka Str., 31-202 Kraków;
tel. +48 (12) 614 33 99; 614 34 88; fax. +48 (12) 614 34 88
e-mail: [email protected]
www.crcd.eu
CCR1, CCR3, CCR9 and DARC. The expression of DARC receptor was proven in the
endothelium [7]. Significant correlation between chemokine RANTES, as well as
CCL18/PARC and CCL3/MIP-1α level and mortality risk in patients with acute coronary
syndromes (including UA patients) was proven [8,13]. Chemokine RANTES activity
increases in patients with myocardial infarction, especially complicated by left ventricular
heart failure (LVEF <35%) [9]. In animal studies positive results occurring in reduction of
myocardial injury after myocardial infarction as well as reduction of patients with heart
failure after monoclonal antibody antiCCL5 mAb and RANTES inhibitors administration
were found. The protective effect was observed due to the smaller migration of leucocyte to
the site of myocardial injury [10,11].
In the ARIC study a significant correlation between
RANTES level and IMT was found [12]. On the other hand Cavusoglu et al. in evaluation of
patients undergoing coronarography has shown that low RANTES level in peripheral blood is
an independent predictor of mortality and MI in patients without previous MI. In the diabetes
subgroup of patients this correlation was also proven [14]. In animal studies high RANTES
expression in the adipose tissue was found to play an important role in the inflammatory cell
reqruitment to the site of injury which was proven to modify endothelial function [15,16].
Discussion
According to previous studies, low serum RANTES levels were associated with more
advanced coronary atherosclerosis and were an independent predictor of poor outcome in
terms of cardiovascular mortality and acute myocardial infarction [17, 18]. On the other hand
Kraaijeveld et al. showed, that higher RANTES levels were observed in patients with
persistent angina, compared to those without clinical symptoms [13].
There were also
positive correlations of RANTES levels and volume of an atherosclerotic plaque in patients
with carotid atherosclerosis published [19].
Summary
However data on RANTES levels and their correlations are equivocal. Chemokine
RANTES/CCL5 role in atherosclerosis is confirmed, and recent research focuses on its gene
polimorphisms and their predictive role as risk factor of coronary artery disease
John Paul II Hospital in Kraków
Jagiellonian University, Institute of Cardiology
80 Prądnicka Str., 31-202 Kraków;
tel. +48 (12) 614 33 99; 614 34 88; fax. +48 (12) 614 34 88
e-mail: [email protected]
www.crcd.eu
Literature
1.
Graham, I. et al. "European guidelines on cardiovascular disease prevention in clinical
practice: executive summary: Fourth Joint Task Force of the European Society
of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical
Practice (Constituted by representatives of nine societies and by invited experts)." Eur
Heart J, 2007, 28(19): 2375-2414.
2. Podolec P., et al. Podręcznik Polskiego Forum Profilaktyki, tom 1, Kraków, 2007, tom 2,
Kraków 2010.
3. Perk J. et. al European Guidelines on Cardiovascular Disease Prevention in Clinical
Practice (Version 2012) : The Fifth Joint Task Force of the European Society
of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical
Practice (Constituted by Representatives of Nine Societies and by Invited Experts). Int J
Behav Med. 2012 Oct 24.
4. Wilcox JN, Nelken NA, Coughlin SR, Gordon D, Schall TJ (1994) Local expression of
inflammatory cytokines in human atherosclerotic plaques. J Atheroscler Thromb 1 Suppl
1: S10–13.
5. Reape TJ, Rayner K, Manning CD, Gee AN, Barnette MS, et al. (1999) Expression and
cellular localization of the CC chemokines PARC and ELC in human atherosclerotic
plaques. Am J Pathol 154: 365–374.
6. Hagg DA, Olson FJ, Kjelldahl J, Jernas M, Thelle DS, et al. (2009) Expression of
chemokine (C-C motif) ligand 18 in human macrophages and atherosclerotic plaques.
Atherosclerosis 204: e15–20.
7. O'Brien, A.D., et al., Chemotaxis of alveolar macrophages in response to signals derived
from alveolar epithelial cells. J Lab Clin Med, 1998. 131(5): p. 417-24.
John Paul II Hospital in Kraków
Jagiellonian University, Institute of Cardiology
80 Prądnicka Str., 31-202 Kraków;
tel. +48 (12) 614 33 99; 614 34 88; fax. +48 (12) 614 34 88
e-mail: [email protected]
www.crcd.eu
8. de Jager SC, et.al. Chemokines CCL3/MIP1α, CCL5/RANTES and CCL18/PARC are
Independent Risk Predictors of Short-Term Mortality in Patients with Acute Coronary
Syndromes. PLoS One. 2012;7(9).
9. Parissis, J.T., et al., Serum profiles of C-C chemokines in acute myocardial infarction:
possible implication in postinfarction left ventricular remodeling. J Interferon Cytokine
Res, 2002. 22(2): p. 223-9
10. Montecucco, F., et al., CC chemokine CCL5 plays a central role impacting infarct size
and post-infarction heart failure in mice. Eur Heart J, 2011.
11. Braunersreuther, V., et al., A novel RANTES antagonist prevents progression
of established atherosclerotic lesions in mice. Arterioscler Thromb Vasc Biol, 2008.
28(6): p. 1090-6.
12. Virani, S.S., et al., Relationship between circulating levels of RANTES (regulated on
activation, normal T-cell expressed, and secreted) and carotid plaque characteristics: the
Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study. Eur Heart J, 2011.
32(4): p. 459-68.
13. Kraaijeveld, A.O., et al., CC chemokine ligand-5 (CCL5/RANTES) and CC chemokine
ligand-18 (CCL18/PARC) are specific markers of refractory unstable angina pectoris and
are transiently raised during severe ischemic symptoms. Circulation, 2007. 116(17): p.
1931-41.
14. Cavusoglu, E., et al., Low plasma RANTES levels are an independent predictor
of cardiac mortality in patients referred for coronary angiography. Arterioscler Thromb
Vasc Biol, 2007. 27(4): p. 929-35.
15. Guzik, T.J., et al., Role of the T cell in the genesis of angiotensin II induced
hypertension and vascular dysfunction. J Exp Med, 2007. 204(10): p. 2449-60.
16. Guzik, T.J., et al., Perivascular adipose tissue as a messenger of the brain-vessel axis:
John Paul II Hospital in Kraków
Jagiellonian University, Institute of Cardiology
80 Prądnicka Str., 31-202 Kraków;
tel. +48 (12) 614 33 99; 614 34 88; fax. +48 (12) 614 34 88
e-mail: [email protected]
www.crcd.eu
role in vascular inflammation and dysfunction. J Physiol Pharmacol, 2007. 58(4): p. 591610.
17. Rothenbacher D, et al. Lifetime physical activity patterns and risk of coronary heart
disease. Heart. 2006 Sep;92(9):1319-20.
18. Cavusoglu, E., et al., Low plasma RANTES levels are an independent predictor of
cardiac mortality in patients referred for coronary angiography. Arterioscler Thromb
Vasc Biol, 2007. 27(4): p. 929-35.
19. Herder C, et al. RANTES/CCL5 and risk for coronary events: results from the
MONICA/KORA Augsburg case-cohort, Athero-Express and CARDIoGRAM studies.
PLoS One. 2011;6(12):e25734.
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John Paul II Hospital in Kraków
Jagiellonian University, Institute of Cardiology
80 Prądnicka Str., 31-202 Kraków;
tel. +48 (12) 614 33 99; 614 34 88; fax. +48 (12) 614 34 88
e-mail: [email protected]
www.crcd.eu