Genetic deletion or pharmacological inhibition of dipeptidyl peptidase-4 improves cardiovascular outcomes after myocardial infarction in mice.
OBJECTIVE
Glucagon-like peptide-1 (7-36)amide (GLP-1) is cleaved by dipeptidyl peptidase-4 (DPP-4) to GLP-1 (9-36)amide. We examined whether chemical inhibition or genetic elimination of DPP-4 activity affects cardiovascular function in normoglycemic and diabetic mice after experimental myocardial infarction.


METHODS
Cardiac structure and function was assessed by hemodynamic monitoring and echocardiography in DPP-4 knockout (Dpp4(-/-)) mice versus wild-type (Dpp4(+/+)) littermate controls and after left anterior descending (LAD) coronary artery ligation-induced myocardial infarction (MI). Effects of sustained DPP-4 inhibition with sitagliptin versus treatment with metformin were ascertained after experimental MI in a high-fat diet-streptozotocin model of murine diabetes. Functional recovery from ischemia-reperfusion (I/R) injury was measured in isolated hearts from Dpp4(-/-) versus Dpp4(+/+) littermates and from normoglycemic wild-type (WT) mice treated with sitagliptin or metformin. Cardioprotective signaling in the murine heart was examined by RT-PCR and Western blot analyses.


RESULTS
Dpp4(-/-) mice exhibited normal indexes of cardiac structure and function. Survival post-MI was modestly improved in normoglycemic Dpp4(-/-) mice. Increased cardiac expression of phosphorylated AKT (pAKT), pGSK3beta, and atrial natriuretic peptide (ANP) was detected in the nonischemic Dpp4(-/-) heart, and HO-1, ANP, and pGSK3beta proteins were induced in nonischemic hearts from diabetic mice treated with sitagliptin or metformin. Sitagliptin and metformin treatment of wild-type diabetic mice reduced mortality after myocardial infarction. Sitagliptin improved functional recovery after I/R injury ex vivo in WT mice with similar protection from I/R injury also manifest in hearts from Dpp4(-/-) versus Dpp4(+/+) mice.


CONCLUSIONS
Genetic disruption or chemical inhibition of DPP-4 does not impair cardiovascular function in the normoglycemic or diabetic mouse heart.
Sauvé
Meghan
M
Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
Ban
Kiwon
K
Momen
M Abdul
MA
Zhou
Yu-Qing
YQ
Henkelman
R Mark
RM
Husain
Mansoor
M
Drucker
Daniel J
DJ
D000818:Animals; D008297:Male; D051379:Mice; D002319:Cardiovascular System / Q000503:physiopathology; D003331:Coronary Vessels / Q000601:surgery; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D018819:Dipeptidyl Peptidase 4 / Q000172:deficiency; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use; D017353:Gene Deletion; D006321:Heart / Q000187:drug effects / Q000502:physiology; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D008687:Metformin / Q000627:therapeutic use; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000401:mortality / Q000503:physiopathology; D011719:Pyrazines / Q000627:therapeutic use; D012016:Reference Values; D015424:Reperfusion; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000627:therapeutic use
D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D008687:Metformin; D011719:Pyrazines; D000068900:Sitagliptin Phosphate; D014230:Triazoles