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

Zhong, Jixin; Rajagopalan, Sanjay

Transient engineered cell-based or plasmid-based overexpression of SDF-1 in ischemic cardiomyopathy has been shown to improve cardiac function in animal models (62) . In a study that compared the effects of SDF-1 overexpressed on MSCs alone or mesenchymal stem cells engineered to overexpress SDF-1 (MSC-SDF) on cardiac function in Lewis rats after acute myocardial infarction, tail vein infusion of MSC and MSC-SDF-1, 1 day after acute myocardial infarction, led to improved cardiac function by echocardiography by 70.7 and 238.8%, respectively, compared with saline controls. The beneficial effects of MSC-SDF transplantation were suggested to be mediated through preservation rather than regeneration of cardiac myocytes within the infarct area (84) . Cardiac progenitor cell and CXCR4 expression on cardiac myocytes are required for further local trophic effects of MSC (85) . The mechanism of action of SDF-1 overexpression in myocardial infarction and heart failure are likely multifactorial, including both systemic and direct trophic effects. An important effect of SDF-1 is its effect on the recruitment of CSCs to the infarct and infarct border zone (59) . Delivery of MSCs engineered to overexpress SDF-1 at the time of acute myocardial infarction has been shown to lead to improvement in cardiac function (61) . The myocardial repair initiated by endogenous stem cell appears blunted because of the natural short-term expression of SDF-1 at the time of acute myocardial infarction. In light of these effects in regulation of SDF-1, DPP4 inhibition has been suggested to be of potential benefit in cardiovascular diseases, such as myocardial infarction and peripheral artrerial disease. In combination with G-CSF, DPP4 inhibition augments myocardial regeneration and improves cardiac function after myocardial infarction in mice (86, 87) . In combination with CXCR4 overexpression, diprotin A treatment has shown to improve myocardial function and repair of infarcted myocardium (88) . A bioengineered protease-resistant form of SDF-1 has shown greater potency in promoting blood flow recovery after hind-limb ischemia (89) and improving cardiac function as well as capillary density in the infarcted heart (34) . Dual injection of G-CSF and sitagliptin resulted in the mobilization of progenitor cells and relieved the symptom of end-stage heart failure in a 19-month-old boy (90) . Protease-resistant forms of SDF-1 display an enhanced potency in improving blood flow in experimental peripheral artery disease and myocardial infarction (34, 89) . It has been shown that parathyroid hormone treatment after myocardial infarction improves DPP4 in chemotaxis and cardiovascular disease Frontiers in Immunology | www.frontiersin.org survival and myocardial function with potential involvement of enhanced homing of bone marrow-derived stem cells. Huber et al. demonstrated that parathyroid hormone serves as a DPP4 inhibitor and increases cardiac SDF-1 level, which in turn enhances CXCR4 + bone marrow-derived stem cell homing to ischemic heart and attenuates ischemic cardiomyopathy after infarction (91) . Haverslag showed SDF-1 preservation by DPP4 inhibitor increases monocyte extravasation and thus accelerating perfusion recovery without detrimental side effects on plaque stability in atherosclerosis-prone ApoE −/− mice (92) . Figure 1 depicts modulation of SDF-1 levels in the myocardium by DPP4 inhibition and enhancement of myocardial angiogenesis by DPP4 levels. In a porcine mo