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SHR Neuro Krebs Kardio Lipid Stoffw Microb

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; 145:64-80 Doi: 10.1016/j.bcp.2017.08.021 [OPEN ACCESS]
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Führende Autor*innen der Med Uni Graz
Kolesnik Ewald
Koyani Chintan Navinchandra
Malle Ernst
Pelzmann Brigitte
Co-Autor*innen der Med Uni Graz
Groschner Klaus
Hammer Astrid
Hinteregger Helga
Lang Petra
Mächler Heinrich
Rainer Peter
Sattler Wolfgang
Scherübel-Posch Susanne
Shrestha Niroj
Sourij Harald
von Lewinski Dirk
Zorn-Pauly Klaus

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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.
Find related publications in this database (using NLM MeSH Indexing)
Adamantane - analogs & derivatives, toxicity
Aged - administration & dosage
Animals - administration & dosage
Cell Line - administration & dosage
Dipeptides - toxicity
Dipeptidyl Peptidase 4 - genetics, metabolism
Dipeptidyl-Peptidase IV Inhibitors - pharmacology
Female - administration & dosage
Gene Expression Regulation, Enzymologic - drug effects, physiology
Heart Atria - cytology
Heart Diseases - metabolism
Humans - administration & dosage
Male - administration & dosage
Mice - administration & dosage
Middle Aged - administration & dosage
Myocardial Contraction - drug effects
Myocytes, Cardiac - drug effects, enzymology

Find related publications in this database (Keywords)
Na+-Ca2+ exchanger
Protein kinase C
Ca2+ transient
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