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Dipeptidyl Peptidase‐4 (DPP‐4) inhibition with linagliptin reduces the induction of proinflammatory/profibrotic TRAF3IP2 in the hearts of female mice fed a Western Diet
Author(s) -
Aroor Annayya,
Kandikattu Hemanthkumar,
Habibi Javad,
Garro Mona,
Klein Thomas,
Sowers James R,
Valente Anthony J,
DeMarco Vincent,
Bysani Chandrasekar
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.977.8
Subject(s) - linagliptin , proinflammatory cytokine , endocrinology , medicine , fibrosis , inflammation , p38 mitogen activated protein kinases , kinase , biology , protein kinase a , diabetes mellitus , type 2 diabetes , microbiology and biotechnology
Recently we reported that the cytoplasmic adapter molecule TRAF3 Interacting Protein 2 (TRAF3IP2) is a major mediator of myocardial inflammation, hypertrophy, fibrosis, and dysfunction induced by chronic activation of the renin‐angiotensin‐aldosterone system. Whether TRAF3IP2 and its downstream intermediates contribute to western diet (WD)‐induced myocardial fibrosis and dysfunction is not known. We have previously reported that the DPP‐4 inhibitor linagliptin prevents diastolic dysfunction and myocardial fibrosis in female mice fed a western diet (WD) high in fat and refined sugars. We hypothesized that WD induces myocardial overexpression of TRAF3IP2 and activation of downstream signaling intermediates, and their induction can be prevented by linagliptin. We fed 4‐week old mice a WD with or without linagliptin (83mg•kg −1 diet) for 16 weeks, and evaluated diastolic function, cardiac TRAF3IP2 expression, transcription factor and p38 MAP kinase activation. WD feeding induced a two‐fold increase in TRAF3IP2 expression, with similar increases in the activation of pro‐inflammatory and pro‐fibrotic transcription factors p65 (Ser 536 ) and c‐Jun (Ser 63 ), and the stress‐activated kinase p38 MAPK (Thr 180 /Thy 182 ). Importantly, linagliptin inhibited their activation. Our results demonstrate for the first time the induction of myocardial TRAF3IP2 protein expression and downstream proinflammatory/profibrotic signaling intermediates in a translationally relevant model of diet‐induced obesity. Therapeutic targeting of DPP‐4 with linagliptin or pharmacological inhibition of TRAF3IP2 may be a promising strategy for prevention of cardiac inflammation, dysfunction and fibrosis in females with obesity/diabetes. Support or Funding Information This work was supported by unrestricted funding from Boehringer Ingelheim (VGD). Additional support was provided by the National Institutes of Health [R01‐HL073101 RO1‐HL107910 to JRS], Veterans Affairs Merit System (I01‐BX002255 to BC and 0018 to JRS).