The CXCL12/CXCR4 chemokine ligand/receptor axis in cardiovascular disease

Abstract

The chemokine receptor CXCR4 and its ligand CXCL12 play an important homeostatic function by mediating the homing of progenitor cells in the bone marrow and regulating their mobilization into peripheral tissues upon injury or stress. Although the CXCL12/CXCR4 interaction has long been regarded as a monogamous relation, the identification of the pro-inflammatory chemokine macrophage migration inhibitory factor (MIF) as an important second ligand for CXCR4, and of CXCR7 as an alternative receptor for CXCL12, has undermined this interpretation and has considerably complicated the understanding of CXCL12/CXCR4 signaling and associated biological functions. This review aims to provide insight into the current concept of the CXCL12/CXCR4 axis in myocardial infarction (MI) and its underlying pathologies such as atherosclerosis and injury-induced vascular restenosis. It will discuss main findings from in vitro studies, animal experiments and large-scale genome-wide association studies. The importance of the CXCL12/CXCR4 axis in progenitor cell homing and mobilization will be addressed, as will be the function of CXCR4 in different cell types involved in atherosclerosis. Finally, a potential translation of current knowledge on CXCR4 into future therapeutical application will be discussed.

Imaging the Cytokine Receptor CXCR4 in Atherosclerotic Plaques with the Radiotracer 68Ga-Pentixafor for PET

“…68 Ga-pentixafor is the first PET agent that exhibits high affinity and selectivity for C-X-C chemokine receptor type 4 (CXCR4) (5). The CXCR4 is a constitutive cytokine receptor involved in several biologic processes including the entry of HIV, the development of metastasis, and the evolution of different autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis (6). CXCR4 expression has been identified in more than 30 different types of cancers, and its activation is a key trigger for enhanced tumor growth and progression, tumor invasiveness, and metastasis.…”

“…Proof-of-concept studies have recently been performed with 68 Ga-pentixafor in patients with lymphoma (8) and multiple myeloma (9), both tumor entities expressing high levels of CXCR4, and demonstrated intense uptake in tumor cells, excellent pharmacokinetics, and favorable dosimetry in humans (10), with a low residual signal in the blood. Furthermore, CXCR4 plays a pivotal role in the trafficking of inflammatory cells by mediating the homing of progenitor cells in the bone marrow and regulating their mobilization into peripheral tissues on injury (6). In fact, the small molecular antagonist AMD3100 (plerixafor) blocks the CXCR4 receptor and allows for mobilization of hematopoietic stem and progenitor cells in the bone marrow for autografting on myeloablative treatment (11).…”

“…The precise role of CXCR4 expression in atherosclerosis is complex and remains controversial (6). CXCR4 might play a proatherogenic role in attracting leukocytes in plaques but may also have a protective role through the recruitment of endothelial cells.…”

A survey of sub-Saharan gene flow into the Mediterranean at risk loci for coronary artery disease

“…This region includes CXCL12, a gene that codes for a chemokine ligand linked to cardiovascular disease with protective effects. 23 It is also worth noting that potential signals of balancing selection have been identified at 10q11, 8 implying that natural selection could have maintained this signal of Sub-Saharan gene flow in this genomic region by favouring admixed individuals against cardiovascular disease. Further research is warranted to shed more light on this hypothesis.…”

Human Breast Adipose-Derived Stem Cells Transfected with the Stromal Cell-Derived Factor-1 Receptor CXCR4 Exhibit Enhanced Viability in Human Autologous Free Fat Grafts

“…Chemokines usually bind to multiple receptors, and the same receptor may bind to more than one chemokine. However, stromal cell derived factor-1 (SDF-1), which binds exclusively to CXCR4, is an exception to this rule [17]. Recently, a new putative receptor for SDF-1, termed CXCR7 and also known as RDC1 and GPR159, has been described [18]; however, its potential role in the regulation of cell trafficking awaits confirmation by other laboratories.…”