Dipeptidyl Peptidase-4 Regulation of SDF-1/CXCR4 Axis: Implications for Cardiovascular Disease

Zhong, Jixin; Rajagopalan, Sanjay

Stromal cell-derived factor-1 is an 8-kDa peptide that is encoded by Cxcl12 (36) . It is a chemoattractant for T lymphocytes, bone marrow stem cells [such as HSC, endothelial progenitor cell (EPC), and mesenchymal stem cells (MSCs)], endogenous cardiac stem cells (CSCs), and adipose-derived regenerative cells (37) (38) (39) . There are several isoforms of SDF-1 (SDF-1α-ζ), resulting from alternative splicing of its mRNA (40) . Among these isoforms, SDF-1α is the best described. SDF-1α is expressed in many tissues, including bone marrow, heart, liver, kidney, thymus, spleen, skeletal muscle, and brain (36, (40) (41) (42) (43) . In the cardiovascular system, SDF-1α is expressed in stromal cells, endothelial cells, and cardiomyocytes (44, 45) . SDF-1 is typically inactivated by exopeptidases, such as DPP4, matrix metalloproteinase (MMP)-2, and -9 (34) . Unlike cleavage of SDF-1 by DPP4 at position 2-3, MMPs cleave SDF-1 at position 4-5, leading to the loss of its binding activity to CXCR4 (46) . The relative contribution of each of these peptidases in regulation of SDF-1 levels is unclear. CXCR4 is an alpha-chemokine receptor specific for SDF-1 and belongs to a family of G-protein-coupled receptors. CXCR4 is expressed on a range of progenitor cells (including hematopoietic, endothelial, and CSCs) and thus is important for cell migration and organ development during embryogenesis (39, 40, 47) . Mice deficient for either CXCR4 or SDF-1 display abnormal B-lymphocyte, hepatic, and cardiac (ventricular septal defects) development, and die in utero (48) (49) (50) . Loss-of-function CXCR4 mutations in humans also causes impaired neutrophil mobilization and B-cell lymphopenia (51) . In addition to CXCR4, CXCR7 has also been suggested to be an important receptor for SDF-1 (52, 53) . However, the relative contribution and interactions of CXCR4 and CXCR7 is not fully elucidated. The involvement of CXCR7 in cardiovascular disease, if any, is also not yet known (39) . DPP4 may also play a more general role in regulating CSF activity and stem cell homing (35) . It was previously believed that disruption of the interaction between CXCR4 receptor expressed by hematopoietic progenitors and SDF-1 expressed by bone marrow stromal cells is sufficient to detach anchored progenitors from their bone marrow niches, leading to their rapid mobilization to the peripheral blood. AMD3100 (also termed plerixafor) inhibits SDF-1-mediated migration in vitro by blocking the chemokine binding to its major receptor CXCR4 (54) . AMD 3100 mobilizes immature progenitor cells from the bone marrow into the blood and has been approved for clinical mobilization in lymphoma and multiple myeloma patients undergoing autologous transplantation. When combined with G-CSF, AMD3100 synergistically augments mobilization of progenitor cells, with increased in vitro migration to SDF-1 gradients and facilitates repopulation of transplanted non-obese diabetic/severe combined immunodeficient mice (55) . AMD 3100 has recently been shown to directly induce SDF-1 release from CXCR4 + human bone marrow osteoblasts and endothelial cells, with SDF-1 release from these cells into the circulation, representing a pivotal mechanism essential for steady-state egress and rapid mobilization of HPCs (56).