Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction.
Ischemic cardiomyopathy is one of the main causes of death, which may be prevented by stem cell-based therapies. SDF-1alpha is the major chemokine attracting stem cells to the heart. Since SDF-1alpha is cleaved and inactivated by CD26/dipeptidylpeptidase IV (DPP-IV), we established a therapeutic concept--applicable to ischemic disorders in general--by combining genetic and pharmacologic inhibition of DPP-IV with G-CSF-mediated stem cell mobilization after myocardial infarction in mice. This approach leads to (1) decreased myocardial DPP-IV activity, (2) increased myocardial homing of circulating CXCR-4+ stem cells, (3) reduced cardiac remodeling, and (4) improved heart function and survival. Indeed, CD26 depletion promoted posttranslational stabilization of active SDF-1alpha in heart lysates and preserved the cardiac SDF-1-CXCR4 homing axis. Therefore, we propose pharmacological DPP-IV inhibition and G-CSF-based stem cell mobilization as a therapeutic concept for future stem cell trials after myocardial infarction.
Zaruba
Marc-Michael
MM
Medical Department I, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
Theiss
Hans Diogenes
HD
Vallaster
Markus
M
Mehl
Ursula
U
Brunner
Stefan
S
David
Robert
R
Fischer
Rebekka
R
Krieg
Lisa
L
Hirsch
Eva
E
Huber
Bruno
B
Nathan
Petra
P
Israel
Lars
L
Imhof
Axel
A
Herbach
Nadja
N
Assmann
Gerald
G
Wanke
Ruediger
R
Mueller-Hoecker
Josef
J
Steinbeck
Gerhard
G
Franz
Wolfgang-Michael
WM