Linagliptin prevents left ventricular stiffening by reducing titin cleavage and hypophosphorylation

I. Cuijpers, A.P. Papageorgiou, P. Carai, M. Herwig, A. Mugge, T. Klein, N. Hamdani, E.A.V. Jones, S. Heymans*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Web of Science)

Abstract

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.
Original languageEnglish
Pages (from-to)729-741
Number of pages13
JournalJournal of Cellular and Molecular Medicine
Volume25
Issue number2
DOIs
Publication statusPublished - 1 Jan 2021

Keywords

  • cardiac dysfunction
  • cardiomyocyte passive stiffness
  • diastolic dysfunction
  • dipeptidyl peptidase-4
  • heart-failure
  • inhibitor linagliptin
  • left ventricular stiffening
  • linagliptin
  • metabolic syndrome
  • muscle
  • myocardial titin
  • pressure
  • protein
  • stiffness
  • titin
  • INHIBITOR LINAGLIPTIN
  • PROTEIN
  • MUSCLE
  • MYOCARDIAL TITIN
  • PRESSURE
  • HEART-FAILURE
  • CARDIAC DYSFUNCTION
  • DIASTOLIC DYSFUNCTION
  • DIPEPTIDYL PEPTIDASE-4
  • STIFFNESS

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