Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
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]
Web of Science
PubMed
FullText
FullText_MUG
- 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
- Altmetrics:
- Dimensions Citations:
- Plum Analytics:
- Scite (citation 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.
- 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)
- DPP-4
- SERCA2a
- Na+-Ca2+ exchanger
- Protein kinase C
- CaMKII
- Ca2+ transient