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. RESEARCH DESIGN AND METHODS--Cardiac structure and function was assessed by hemodynamic monitoring and echocardiography in DPP-4 knockout ([Dpp4.sup.-/-]) mice versus wild-type ([Dpp4.sup.+/+]) littermate controls and after left anterior descending (LAD) coronary artery ligation-induced myocardial infarction (MI). Effects of sustained DPP-4 inhibition with sita-gliptin 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.sup.-/-] versus [Dpp4.sup.+/+] 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.sup.-/-] mice exhibited normal indexes of cardiac structure and function. Survival post-MI was modestly improved in normoglycemic [Dpp4.sup.-/-] mice. Increased cardiac expression of phosphorylated AKT (pAKT), pGSK3β, and atrial natriuretic peptide (ANP) was detected in the nonischemic [Dpp4.sup.-/-] heart, and HO-1, ANP, and pGSK3β 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.sup.-/-] versus [Dpp4.sup.+/+] mice. CONCLUSIONS--Genetic disruption or chemical inhibition of DPP-4 does not impair cardiovascular function in the normoglycemic or diabetic mouse heart.
Type 2 diabetes is associated with an increased risk of cardiovascular disease, hence there is considerable interest in strategies that reduce cardiovascular morbidity and mortality in diabetic subjects. Although aggressive [...]