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

Zhong, Jixin; Rajagopalan, Sanjay

The SDF-1/CXCR4 axis has been shown to be critical in tissue repair in multiple organ systems, including the eye, heart, kidney, liver, brain, and skin. Specific to the heart, the SDF-1/CXCR4 axis has been shown to be essential for cardiogenesis (57, 58) . SDF-1 is now well known as a key regulator of stem cell migration to sites of tissue injury (44, 59) . SDF-1 was first identified by Askari et al. as a key regulator of stem cell migration to ischemic cardiac tissue (44) . CD34 + stem cells express the SDF-1 receptor CXCR4 at high levels (37, 60) . During myocardial infarction, SDF-1 levels are elevated 1 h after infarction and return to baseline at day 7 and further reduced to a low level thereafter (44) . Overexpression of SDF-1 in ischemic cardiomyopathy by either engineered cellbased or plasmid-based approach improved cardiac function in rats via enhancing stem cell homing and promoting revascularization of the infarct area (61, 62) . Therefore, the ability to express SDF-1 locally is believed to enhance the vasculogenic potential of adult cardiac progenitor cells (63) . However, the enhancement of endogenous stem cell-based repair appears to be blunted due to the short half-life of SDF-1 at the time of acute myocardial infarction owing to its degradation by proteases (44) . As a major enzyme mediating the degradation of SDF-1, DPP4 may represent a potential target for improving stem cell homing with stem cell-based therapy. Preservation of SDF-1 by DPP4 inhibition has been shown to promote stem cell repopulation and homing to ischemic tissues. DPP4 inhibitors diprotin A or Val-Pyr, enhance chemotaxis of HSCs and HPCs and greatly increase homing and engrafting capacity of HSCs (64, 65) . Pretreatment of HSC with DPP4 inhibitor diprotin A, enhanced their repopulation ability in lethally irradiated mice (66) . Enhancement of engraftment of human CD34 + cord blood cells with DPP4 inhibition has also been observed in xenogeneic mouse recipients (NOD/SCID or NOD/SCID/beta 2 null ) (67, 68) . Pretreating either donor cells in vitro or recipients in vivo is able to enhance the engraftment of stem cells (66, 69) . In a lung transplantation model, systemic DPP4 inhibition by vildagliptin increases SDF-1 levels in plasma, spleen, and lung, accompanied by a significant increase of stem cells in the lung grafts. DPP4 inhibitor-treated mice also shows less alveolar edema compared with untreated recipients (70) . Liebler showed that DPP4 inhibition enhances SDF-1/CXCR4 axis and increased the retention of human bone marrow-derived cells in the injured lungs of immune deficient mice by 30% (71) . In addition to SDF-1, DPP4 inhibition also enhances bone marrow engraftment by preserving G-CSF and GM-CSF. Both G-CSF and GM-CSF are substrates for DPP4, with inhibition of DPP4 promotes bone marrow engraftment not only through SDF-1 but also CSF-dependent mechanisms (35) . G-CSF and GM-CSF in turn may also increase the expression of DPP4 on CD34 + cells, which results in their decreased responsiveness to SDF-1 (72).