Chronic AMD3100 antagonism of SDF-1alpha-CXCR4 exacerbates cardiac dysfunction and remodeling after myocardial infarction.
The role of the SDF-1alpha-CXCR4 axis in response to myocardial infarction is unknown. We addressed it using the CXCR4 antagonist, AMD3100, to block SDF-1alpha interaction with CXCR4 after chronic coronary artery ligation. Chronic AMD3100 treatment decreased ejection fraction and fractional shortening in mice 20days after myocardial infarction compared with vehicle-treated mice (echocardiography). Morphometric analysis showed hearts of AMD3100-treated infarcted mice to have expanded scar, to be hypertrophic (confirmed by myocyte cross-section area) and dilated, with increased LV end systolic and end diastolic dimensions, and to have decreased scar collagen content; p-AKT levels were attenuated and this was accompanied by increased apoptosis. Despite increased injury, c-kit(pos) cardiac progenitor cells (CPCs) were increased in the risk region of AMD3100-treated infarcted mice; CPCs were CD34(neg)/CD45(neg) with the majority undergoing symmetric cell division. c-kit(pos)/MHC(pos) CPCs also increased in the risk region of the AMD3100-treated infarcted group. In this group, GSK-3beta signaling was attenuated compared to vehicle-treated, possibly accounting for increased proliferation and increased cardiac committed MHC(pos) CPCs. Increased proliferation following AMD3100 treatment was supported by increased levels of cyclin D1, a consequence of increased prolyl isomerase, Pin1, and decreased cyclin D1 phosphorylation. In summary, pharmacologic antagonism of CXCR4 demonstrates that SDF-1alpha-CXCR4 signaling plays an important role during and after myocardial infarction and that it exerts pleiotropic salubrious effects, protecting the myocardium from apoptotic cell death, facilitating scar formation, restricting CPC proliferation, and directing CPCs toward a cardiac fate.
Dai
Shujing
S
Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40202, USA.
Yuan
Fangping
F
Mu
Jingyao
J
Li
Chengxin
C
Chen
Ning
N
Guo
Shangzhi
S
Kingery
Justin
J
Prabhu
Sumanth D
SD
Bolli
Roberto
R
Rokosh
Gregg
G
D000818:Animals; D001596:Benzylamines; D015153:Blotting, Western; D054377:Chemokine CXCL12 / Q000378:metabolism*; D000080027:Cyclams; D019938:Cyclin D1 / Q000378:metabolism; D004452:Echocardiography; D006571:Heterocyclic Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism*; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D001596:Benzylamines; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019718:Receptors, CXCR4; D019938:Cyclin D1; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse; C088327:plerixafor