Genetic Deletion or Pharmacological Inhibition of Dipeptidyl Peptidase-4 Improves Cardiovascular Outcomes After Myocardial Infarction in Mice

  1. Daniel J. Drucker1
  1. 1Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada;
  2. 2Toronto General Hospital, the Heart & Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, and the Departments of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada;
  3. 3Mouse Imaging Centre, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
  1. Corresponding author: Daniel J. Drucker, d.drucker{at}utoronto.ca.
  1. M.H. and D.J.D. contributed equally to this work.

Abstract

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−/−) 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), pGSK3β, and atrial natriuretic peptide (ANP) was detected in the nonischemic Dpp4−/− 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−/− versus Dpp4+/+ mice.

CONCLUSIONS Genetic disruption or chemical inhibition of DPP-4 does not impair cardiovascular function in the normoglycemic or diabetic mouse heart.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received June 29, 2009.
    • Accepted January 6, 2010.

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  1. Diabetes vol. 59 no. 4 1063-1073
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