Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

Logo MUG-Forschungsportal

Gewählte Publikation:

SHR Neuro Krebs Kardio Lipid

Koyani, CN; Kolesnik, E; Wölkart, G; Shrestha, N; Scheruebel, S; Trummer, C; Zorn-Pauly, K; Hammer, A; Lang, P; Reicher, H; Maechler, H; Groschner, K; Mayer, B; Rainer, PP; Sourij, H; Sattler, W; Malle, E; Pelzmann, B; von Lewinski, D.
Dipeptidyl peptidase-4 independent cardiac dysfunction links saxagliptin to heart failure.
Biochem Pharmacol. 2017; 145(17-18):64-80 [OPEN ACCESS]
Web of Science PubMed FullText FullText_MUG

 

Autor/innen der Med Uni Graz:
Groschner Klaus
Hammer Astrid
Kolesnik Ewald
Koyani Chintan Navinchandra
Lang Petra
Maechler Heinrich
Malle Ernst
Pelzmann Brigitte
Rainer Peter
Reicher Helga
Sattler Wolfgang
Scherübel Susanne
Shrestha Niroj
Sourij Harald
von Lewinski Dirk
Zorn-Pauly Klaus
Altmetrics:

Dimensions Citations:

Plum Analytics:
Abstract:
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 Ca2+/calmodulin-dependent protein kinase II-phospholamban-sarcoplasmic reticulum Ca2+-ATPase 2a axis and Na+-Ca2+ exchanger function in Ca2+ extrusion. This resulted in reduced sarcoplasmic reticulum Ca2+ content, diastolic Ca2+ 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.
Find related publications in this database (using NLM MeSH Indexing)
Adamantane - analogs & derivatives
Adamantane - toxicity
Aged -
Animals -
Cell Line -
Dipeptides - toxicity
Dipeptidyl Peptidase 4 - genetics
Dipeptidyl Peptidase 4 - metabolism
Dipeptidyl-Peptidase IV Inhibitors - pharmacology
Female -
Gene Expression Regulation, Enzymologic - drug effects
Gene Expression Regulation, Enzymologic - physiology
Heart Atria - cytology
Heart Diseases - metabolism
Humans -
Male -
Mice -
Middle Aged -
Myocardial Contraction - drug effects
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - enzymology

Find related publications in this database (Keywords)
DPP-4
SERCA2a
Na+-Ca2+ exchanger
Protein kinase C
CaMKII
Ca2+ transient
© Meduni Graz Impressum