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Liehn et al.: Chemokines in cardiac repair - Supplemental material
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Online Appendix for the following JACC article
TITLE: Repair After Myocardial Infarction, Between Fantasy and Reality: The Role of
Chemokines
AUTHORS: Elisa A. Liehn, MD, PhD, Otilia Postea, PhD, Adelina Curaj, MD, Nikolaus
Marx, MD
APPENDIX
Chemokines (an assimilation of chemoattractant cytokines) are a family of
structurally related glycoproteins with potent leukocyte activation capacity and
chemotactic activity (1) which share 20 – 50% gene and amino acid sequence
homology with each other. According to the position of the N-terminal cysteines,
chemokines are classified into four subfamilies. The CXC chemokines contain a
single amino acid between the first and second cysteine residues, whereas CC
chemokines have adjacent cysteine residues. The C chemokine group so far consists
of only one member, termed lymphotactin, and lacks one of the cysteines in the four
cysteines motif, but at its carboxyl terminus shares homology with CC chemokines.
The CX3C chemokine fractalkine/neurotactin has three amino acid residues between
the first two cysteines, representing the fourth chemokine subgroup identified.
Chemokines act through an accordingly classified subfamily of G-protein coupled
seven-transmembrane receptors, which interestingly also share 25 – 80% amino acid
sequence identity. In a wide variety of diseases, chemokines have been identified to
play key roles in the initiation and perpetuation of inflammatory processes (2-6).
All known chemokines involved in molecular and cellular events after MI,
including alternative names, receptors, sources and targets, are listed in
supplementary table 1.
Liehn et al.: Chemokines in cardiac repair - Supplemental material
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Liehn et al.: Chemokines in cardiac repair - Supplemental material
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healing and left ventricular remodeling. Cardiovasc Res 2007;74:313-22.
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factor-1alpha plays a critical role in stem cell recruitment to the heart after myocardial
infarction but is not sufficient to induce homing in the absence of injury. Circulation
2004;110:3300-5.
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neointimal hyperplasia after arterial injury in hyperlipidemic mice involves early
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Liehn et al.: Chemokines in cardiac repair - Supplemental material
Supplement table 1. Chemokines and chemokine receptors with decisive roles in MI
Alternative names
Receptors
Source
Target
Effects on infarct healing
CXC Family
CXCL1
CXCL2
- Growth regulated oncogene (GRO)-1 or -α, CXCR2
- Keratinocyte-Derived Chemokine (KC)
CXCR1
- Neutrophil-activating protein (NAP) -3
- Melanoma growth stimulating activity
(MSGA)-α
- Macrophage inflammatory protein (MIP) 2- CXCR2
- Growth regulated oncogene (GRO)-2 or -
CXCL4
- Platelet factor (PF) 4
CXCL6
- Granulocyte chemotactic protein (GPC) 2,
- LPS-induced CXC chemokine (LIX)
CXCL8
- Interleukin (IL) 8
- Neutrophil activating Peptide (NAP) 1
- Neutrophil chemotactic factor (NCF)
- Monocyte derived neutrophil chemotactic
factor (MDNCF)
- T lymphocyte chemotactic factor (TCF)
- Granulocyte chemotactic protein (GCP)
- Leukocyte adhesion inhibitor (LAI)
- Interferon gamma-induced protein (IP) 10
- Cytokine responsive gene (CRG)-2
CXCL10
CXCL12
- Stromal cell-derived factor (SDF)-1a/b
- PreB cell growth stimulatory factor (PBSF)
Melanoma cells, M/Ma,
N, EC
N, M, EC, SMC
- induce neutrophil infiltration after MI (7)
M/Ma
N, M, EC, SMC,
Hematopoietic stem
cells
N, M, EC
- induce neutrophil infiltration after MI (7)
- protective effects of CXCR2 signaling on myocardial
viability (8)
- potent angiostatic factor (9)
N
- the main inducer of neutrophil infiltration after MI (7)
N, EC, Ma,
Mast cells,
Keratinocytes
- antagonist (anti-IL8 antibody) significantly reduces
the necrosis in a rabbit model of myocardial
ischemia–reperfusion without affecting neutrophil (10)
CXCR3b Megakaryocytes,
Platelets
CXCR1 Fibroblasts, Malign cells,
CXCR2 Chondrocytes, EC,
Mesenchymal cells
CXCR1 M/Ma, EC, TC, N,
CXCR2 Fibroblasts, Malign cells,
Chondrocytes,
Keratinocytes,
Hepatocytes
CXCR3
CXCR4
CXCR7
M, EC, SMC,
Fibroblasts,
T lymphocytes,
Splenocytes,
Keratinocytes,
Osteoblasts, Astrocytes
M, EC, SMC, different
organs (heart)
M/ Ma, TC, NK cells, DC, - potent angiostatic, antifibrotic agent, serve to
EC
prevent premature wound angiogenesis
and fibrous tissue deposition (11)
- no role in inflammatory events following myocardial
infarction (12)
TC, M, NK cells,
progenitor cells
- critical role in cardiovascular development and
angiogenesis (13)
- critical role in recruitment of progenitor cells in the
infarcted myocardium (14)
- protect ischemic myocardium, decreasing scar size
and mediating neovascularization in mice and rats
(15,16).
- antagonist (AMD3100) reduced also scar formation
and improved cardiac contractility (17)
Liehn et al.: Chemokines in cardiac repair - Supplemental material
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CC Family
CCL2
- JE/Monocyte chemotactic protein (MCP)-1
- Monocyte chemotactic and activating factor
(MCAF)
CCR2
M, EC, SMA,
Fibroblasts, Malign cells
M, DC
CCL3
- Macrophage inflammatory protein (MIP)-1
TC
CCL5
- Regulated upon Activation, Normal T-cell
Expressed, and Secreted (RANTES)
CCR1
CCR5
CCR1
CCR3
CCR5
M, TC, B cells,
Eosinophils
M, TC,
DC
CCL7
- Monocyte chemotactic protein (MCP)-3
- MARC
- Eotaxin-1
CCR2
CCR3
CCR2
CCR3
CCR5
Ma, Malign cells
CCL11
TC, Platelets,
Leukocytes
SMC
M/Ma, NK cells, TC,
MSC
Eosinophils, B cells,
Mast cell, DC
-antagonists (anti-MCP1 antibody) attenuated postinfarction left ventricular remodeling, at the expense of
a prolonged inflammatory phase and delayed
replacement of injured cardiomyocytes with
granulation tissue (18)
- antagonist (PA508) reduces inflammatory monocyte
recruitment, attenuating myocardial ischemia/
reperfusion injury (19,20)
- induce neutrophil infiltration after MI (21)
- cross-communication of opioid receptors with
chemokine receptors enhancing protection of
myocardium against hypoxia by conferring antiinflammatory effects onto circulating leukocytes (22,23)
- antagonist (MetRANTES44AANA47-RANTES)
reduced myocardial reperfusion injury (3)
- controls the myocardial homing of MSCs after injury (24)
- triggers Mast cell infiltration of the heart and
contributes to myocardial fibrosis; antagonist
(bertilimumab) decreases myocardial fibrosis and
improves contractile function after heart transplantation
(25)
CX3C Family
CX3CL1
- Fraktalkine
- Neurotactin
- ABCD-3
CX3CR1 SMC, EC, Microglia
M, TC, N
- direct cardiodepressive effect on cardiac tissue (26)
- induces resident monocyte accumulation, promoting
angiogenesis and extracellular matrix deposition (27)
Endothelial cells (EC); T cells (TC); Smooth muscle cells (SMC); Monocytes (M); Macrophages (Ma); Neutrophils (N); Dendritic cells (DC);
Mesenchymal stem cells (MSC); Smooth muscle cells (SMC); Natural killer (NK); Dendritic cells (DC).