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


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.


CONCLUSIONS
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.
Department of Internal Medicine I, Ludwig-Maximilians-University, Campus Grosshadern, Marchioninistr. 15, D-81377 Munich, Germany.
Bruno C
BC
Huber
Stefan
S
Brunner
Alexander
A
Segeth
Petra
P
Nathan
Rebekka
R
Fischer
Marc M
MM
Zaruba
Marcus
M
Vallaster
Hans D
HD
Theiss
Robert
R
David
Armin
A
Gerbitz
Wolfgang-Michael
WM
Franz
D053687:Adult Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001596:Benzylamines; D002316:Cardiotonic Agents / Q000494:pharmacology; D054377:Chemokine CXCL12 / Q000378:metabolism*; D000080027:Cyclams; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006571:Heterocyclic Compounds / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control / Q000628:therapy*; D010281:Parathyroid Hormone / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D044968:Regenerative Medicine / Q000379:methods
D001596:Benzylamines; C514936:CXCR4 protein, mouse; D002316:Cardiotonic Agents; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D010281:Parathyroid Hormone; D011480:Protease Inhibitors; D019718:Receptors, CXCR4; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse; C088327:plerixafor