The novel DPP-4 inhibitors linagliptin and BI 14361 reduce infarct size after myocardial ischemia/reperfusion in rats.
BACKGROUND
Dipeptidylpeptidase-4 inhibition is reported to have beneficial effects on myocardial ischemia. Mechanisms might include a reduced degradation of stromal cell-derived factor-1 alpha with subsequent increased recruitment of circulating stem cells and/or incretin receptor-dependent pathways. This study evaluated the novel xanthine-based dipeptidylpeptidase-4 inhibitors linagliptin (BI 1356) and BI 14361 in cardiac ischemia.


METHODS
Male Wistar rats were pretreated with linagliptin or BI 14361 and subjected to ligation of the left anterior descending coronary artery for 30 min.


RESULTS
Dipeptidylpeptidase-4 inhibition significantly reduced the infarct size after 7 days (-27.7%, p<0.05) and 8 weeks (-18.0%, p<0.05). There was a significantly improved maximum rate of left ventricular pressure decline (dP/dt min) in linagliptin-treated animals 8 weeks after ischemia/reperfusion. Apart from that, treatment did not improve cardiac function as determined by echocardiography and cardiac catheterization. Immunohistological staining revealed an increased number of cells positive for stromal cell-derived factor-1 alpha, CXCR-4 and CD34 within and around the infarcted area of BI 14361-treated animals.


CONCLUSIONS
Linagliptin and BI 14361 are able to reduce infarct size after myocardial ischemia. The immunohistological findings support the hypothesis that dipeptidylpeptidase-4 inhibition via reduced cleavage of stromal cell-derived factor-1 alpha might lead to an enhanced recruitment of CXCR-4+ circulating progenitor cells.
Institute of Nutritional Science, University of Potsdam, Potsdam, Germany. hocher@uni-potsdam.de
Berthold
B
Hocher
Yuliya
Y
Sharkovska
Michael
M
Mark
Thomas
T
Klein
Thiemo
T
Pfab
D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000502:physiology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D000069476:Linagliptin; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology; D011687:Purines / Q000737:chemistry / Q000627:therapeutic use*; D011799:Quinazolines / Q000737:chemistry / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D014970:Xanthines / Q000737:chemistry / Q000627:therapeutic use*
C586668:8-(3-amino-1-piperidinyl)-7-(2-butyn-1-yl)-1-((4,6-dimethyl-2-pyrimidinyl)methyl)-3-methylxanthine; D054873:Dipeptidyl-Peptidase IV Inhibitors; D011687:Purines; D011799:Quinazolines; D014970:Xanthines; D000069476:Linagliptin; D018819:Dipeptidyl Peptidase 4