Parathyroid hormone is a DPP-IV inhibitor and increases SDF-1-driven homing of CXCR4(+) stem cells into the ischaemic heart.

AIMS: Parathyroid hormone (PTH) has been shown to promote stem cell mobilization into peripheral blood. Moreover, PTH treatment after myocardial infarction (MI) improved survival and myocardial function associated with enhanced homing of bone marrow-derived stem cells (BMCs). To unravel the molecular mechanisms of PTH-mediated stem cell trafficking, we analysed wild-type (wt) and green fluorescent protein (GFP)-transgenic mice after MI with respect to the pivotal stromal cell-derived factor-1 (SDF-1)/chemokine receptor type 4 (CXCR4) axis. METHODS AND RESULTS: WT and GFP-transgenic mice (C57BL/6J) were infarcted by coronary artery ligation and PTH (80 µg/kg/day) was injected for 6 days afterwards. Number of BMCs was analysed by flow cytometry. SDF-1 protein levels and activity of dipeptidyl peptidase-IV (DPP-IV) were investigated by ELISA and activity assay. Functional analyses were performed at day 30 after MI. PTH-treated animals revealed an enhanced homing of CXCR4(+) BMCs associated with an increased protein level of the corresponding homing factor SDF-1 in the ischaemic heart. In vitro and in vivo, PTH inhibited the activity of DPP-IV, which cleaves and inactivates SDF-1. Functionally, PTH significantly improved myocardial function after MI. Both stem cell homing as well as functional recovery were reversed by the CXCR4 antagonist AMD3100. CONCLUSION: In summary, PTH is a DPP-IV inhibitor leading to an increased cardiac SDF-1 level, which enhances recruitment of CXCR4(+) BMCs into the ischaemic heart associated with attenuated ischaemic cardiomyopathy. Since PTH is already clinically used our findings may have direct impact on the initiation of studies in patients with ischaemic disorders.

Comparison of parathyroid hormone and G-CSF treatment after myocardial infarction on perfusion and stem cell homing.

Mobilization of stem cells by granulocyte colony-stimulating factor (G-CSF) was shown to have protective effects after myocardial infarction (MI); however, clinical trials failed to be effective. In search for alternative cytokines, parathyroid hormone (PTH) was recently shown to promote cardiac repair by enhanced neovascularization and cell survival. To compare the impact of the two cytokines G-CSF and PTH on myocardial perfusion, mice were noninvasively and repetitively investigated by pinhole single-photon emission computed tomography (SPECT) after MI. Mobilization and homing of bone marrow-derived stem cells (BMCs) was analyzed by fluorescence-activated cell sorter (FACS) analysis. Mice (C57BL/6J) were infarcted by left anterior descending artery ligation. PTH (80 mug/kg) and G-CSF (100 mug/kg) were injected for 5 days. Perfusion defects were determined by (99m)Tc-sestamibi SPECT at days 6 and 30 after MI. The number of BMCs characterized by Lin(-)/Sca-1(+)/c-kit(+) cells in peripheral blood and heart was analyzed by FACS. Both G-CSF and PTH treatment resulted in an augmented mobilization of BMCs in the peripheral blood. Contrary to G-CSF and controls, PTH and the combination showed significant migration of BMCs in ischemic myocardium associated with a significant reduction of perfusion defects from day 6 to day 30. A combination of both cytokines had no additional effects on migration and perfusion. In our preclinical model, SPECT analyses revealed the functional potential of PTH reducing size of infarction together with an enhanced homing of BMCs to the myocardium in contrast to G-CSF. A combination of both cytokines did not improve the functional outcome, suggesting clinical applications of PTH in ischemic heart diseases.