Linagliptin prevents left ventricular stiffening by reducing titin cleavage and hypophosphorylation.

Autor: Cuijpers I; Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium.; Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University Medical Center, Maastricht, The Netherlands., Papageorgiou AP; Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium.; Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University Medical Center, Maastricht, The Netherlands., Carai P; Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium., Herwig M; Molecular Cardiology and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany.; Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany.; Institute of Physiology, Ruhr University Bochum, Bochum, Germany., Mügge A; Molecular Cardiology and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany.; Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany., Klein T; Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany., Hamdani N; Molecular Cardiology and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany.; Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany.; Institute of Physiology, Ruhr University Bochum, Bochum, Germany.; Department of Clinical Pharmacology, Ruhr University Bochum, Bochum, Germany., Jones EAV; Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium.; Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University Medical Center, Maastricht, The Netherlands., Heymans S; Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium.; Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University Medical Center, Maastricht, The Netherlands.; Holland Heart House, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands.
Jazyk: angličtina
Zdroj: Journal of cellular and molecular medicine [J Cell Mol Med] 2021 Jan; Vol. 25 (2), pp. 729-741. Date of Electronic Publication: 2020 Dec 09.
DOI: 10.1111/jcmm.16122
Abstrakt: The metabolic syndrome (MetS) is an escalating problem worldwide, causing left ventricular stiffening, an early characteristic of diastolic dysfunction for which no treatment exists. As diastolic dysfunction and stiffening in MetS patients are associated with increased circulating dipeptidyl peptidase-4 (DPP-4) levels, we investigated whether the clinically approved DPP-4 inhibitor linagliptin reduces left ventricular stiffness in MetS-induced cardiac disease. Sixteen-week-old obese ZSF1 rats, displaying the MetS and left ventricular stiffness, received linagliptin-supplemented or placebo diet for four weeks. Linagliptin significantly reduced obesity, hyperlipidaemia, and hyperglycaemia and improved left ventricular relaxation. This improved relaxation was related to decreased cardiac fibrosis and cardiomyocyte passive stiffness (F passive ). The reduced F passive was the result of titin isoform switching from the stiff N2B to the more flexible N2BA and increased phosphorylation of total titin and specifically its N2Bus region (S4080 and S3391). Importantly, DPP-4 directly cleaved titin in vitro, resulting in an increased F passive , which was prevented by simultaneous administration of linagliptin. In conclusion, linagliptin improves left ventricular stiffness in obese ZSF1 rats by preventing direct DPP4-mediated titin cleavage, as well as by modulating both titin isoform levels and phosphorylation. Reducing left ventricular stiffness by administering linagliptin might prevent MetS-induced early diastolic dysfunction in human.
(© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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