Dipeptidyl peptidase-4 independent cardiac dysfunction links saxagliptin to heart failure.

Autor: Koyani CN; Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria., Kolesnik E; Department of Internal Medicine, Division of Cardiology, Medical University of Graz, Austria., Wölkart G; Department of Pharmacology and Toxicology, University of Graz, Austria., Shrestha N; Institute of Biophysics, Medical University of Graz, Austria., Scheruebel S; Institute of Biophysics, Medical University of Graz, Austria., Trummer C; Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria., Zorn-Pauly K; Institute of Biophysics, Medical University of Graz, Austria., Hammer A; Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Austria., Lang P; Institute of Biophysics, Medical University of Graz, Austria., Reicher H; Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria., Maechler H; Division of Cardiac Surgery, Medical University of Graz, Austria., Groschner K; Institute of Biophysics, Medical University of Graz, Austria., Mayer B; Department of Pharmacology and Toxicology, University of Graz, Austria., Rainer PP; Department of Internal Medicine, Division of Cardiology, Medical University of Graz, Austria., Sourij H; Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, Austria; Center for Biomarker Research in Medicine, Graz, Austria., Sattler W; Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria., Malle E; Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria. Electronic address: ernst.malle@medunigraz.at., Pelzmann B; Institute of Biophysics, Medical University of Graz, Austria. Electronic address: brigitte.pelzmann@medunigraz.at., von Lewinski D; Department of Internal Medicine, Division of Cardiology, Medical University of Graz, Austria.
Jazyk: angličtina
Zdroj: Biochemical pharmacology [Biochem Pharmacol] 2017 Dec 01; Vol. 145, pp. 64-80. Date of Electronic Publication: 2017 Aug 30.
DOI: 10.1016/j.bcp.2017.08.021
Abstrakt: Saxagliptin treatment has been associated with increased rate of hospitalization for heart failure in type 2 diabetic patients, though the underlying mechanism(s) remain elusive. To address this, we assessed the effects of saxagliptin on human atrial trabeculae, guinea pig hearts and cardiomyocytes. We found that the primary target of saxagliptin, dipeptidyl peptidase-4, is absent in cardiomyocytes, yet saxagliptin internalized into cardiomyocytes and impaired cardiac contractility via inhibition of the Ca 2+ /calmodulin-dependent protein kinase II-phospholamban-sarcoplasmic reticulum Ca 2+ -ATPase 2a axis and Na + -Ca 2+ exchanger function in Ca 2+ extrusion. This resulted in reduced sarcoplasmic reticulum Ca 2+ content, diastolic Ca 2+ overload, systolic dysfunction and impaired contractile force. Furthermore, saxagliptin reduced protein kinase C-mediated delayed rectifier K + current that prolonged action potential duration and consequently QTc interval. Importantly, saxagliptin aggravated pre-existing cardiac dysfunction induced by ischemia/reperfusion injury. In conclusion, our novel results provide mechanisms for the off-target deleterious effects of saxagliptin on cardiac function and support the outcome of SAVOR-TIMI 53 trial that linked saxagliptin with the risk of heart failure.
(Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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