Dipeptidyl peptidase-4 (DPP-4) inhibition with linagliptin reduces western diet-induced myocardial TRAF3IP2 expression, inflammation and fibrosis in female mice

• Published in: Cardiovascular diabetology Vol. 16; no. 1; p. 61
• Main Authors: Aroor, Annayya R, Habibi, Javad, Kandikattu, Hemanth Kumar, Garro-Kacher, Mona, Barron, Brady, Chen, Dongqing, Hayden, Melvin R, Whaley-Connell, Adam, Bender, Shawn B, Klein, Thomas, Padilla, Jaume, Sowers, James R, Chandrasekar, Bysani, DeMarco, Vincent G
• Format: Journal Article
• Language: English
• Published: England BioMed Central 05.05.2017; BMC
• Subjects: Activation; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Aldosterone; Angiotensin; Angiotensin II; Animal care; Animals; Cardiomyocytes; Cardiomyopathies - enzymology; Cardiomyopathies - etiology; Cardiomyopathies - physiopathology; Cardiomyopathies - prevention & control; Cardiovascular disease; Cells, Cultured; Collagen; Contractility; Diabetes; Diastole; Diastolic dysfunction; Diet; Diet, Western - adverse effects; Dipeptidyl Peptidase 4 - metabolism; Dipeptidyl-peptidase IV; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Disease Models, Animal; Down-Regulation; Ejection; Female; Females; Fibroblasts; Fibrosis; Functional anatomy; Growth factors; Heart diseases; Heart failure; Hypertrophy; Inflammation; Inhibition; Insulin resistance; Intermediates; Ischemia; Kinases; Laboratory animals; Linagliptin; Linagliptin - pharmacology; MAP kinase; Mice; Mice, Inbred C57BL; Migration; Muscle contraction; Myocardial fibrosis; Myocarditis - enzymology; Myocarditis - etiology; Myocarditis - physiopathology; Myocarditis - prevention & control; Myocardium - enzymology; Myocardium - ultrastructure; NF-kappa B - metabolism; Nitrosative Stress - drug effects; Obesity; Obesity - etiology; Original Investigation; Overnutrition; Oxidative stress; Oxidative Stress - drug effects; p38 Mitogen-Activated Protein Kinases - metabolism; Peptidase; Peptides; Rats; Recovery of Function; Renin; Rodents; Signal Transduction - drug effects; Stress; Sugar; Time Factors; TRAF3IP2; Transcription Factor AP-1 - metabolism; Transcription factors; Ventricular Dysfunction, Left - enzymology; Ventricular Dysfunction, Left - physiopathology; Ventricular Dysfunction, Left - prevention & control; Ventricular Function, Left - drug effects; Womens health; Xenografts; Obesity; Diastolic dysfunction; Myocardial fibrosis; Linagliptin; TRAF3IP2
• ISSN: 1475-2840; 1475-2840
• DOI: 10.1186/s12933-017-0544-4

Diastolic dysfunction (DD), a hallmark of obesity and primary defect in heart failure with preserved ejection fraction, is a predictor of future cardiovascular events. We previously reported that linagliptin, a dipeptidyl peptidase-4 inhibitor, improved DD in Zucker Obese rats, a genetic model of obesity and hypertension. Here we investigated the cardioprotective effects of linagliptin on development of DD in western diet (WD)-fed mice, a clinically relevant model of overnutrition and activation of the renin-angiotensin-aldosterone system. Female C56Bl/6 J mice were fed an obesogenic WD high in fat and simple sugars, and supplemented or not with linagliptin for 16 weeks. WD induced oxidative stress, inflammation, upregulation of Angiotensin II type 1 receptor and mineralocorticoid receptor (MR) expression, interstitial fibrosis, ultrastructural abnormalities and DD. Linagliptin inhibited cardiac DPP-4 activity and prevented molecular impairments and associated functional and structural abnormalities. Further, WD upregulated the expression of TRAF3IP2, a cytoplasmic adapter molecule and a regulator of multiple inflammatory mediators. Linagliptin inhibited its expression, activation of its downstream signaling intermediates NF-κB, AP-1 and p38-MAPK, and induction of multiple inflammatory mediators and growth factors that are known to contribute to development and progression of hypertrophy, fibrosis and contractile dysfunction. Linagliptin also inhibited WD-induced collagens I and III expression. Supporting these in vivo observations, linagliptin inhibited aldosterone-mediated MR-dependent oxidative stress, upregulation of TRAF3IP2, proinflammatory cytokine, and growth factor expression, and collagen induction in cultured primary cardiac fibroblasts. More importantly, linagliptin inhibited aldosterone-induced fibroblast activation and migration. Together, these in vivo and in vitro results suggest that inhibition of DPP-4 activity by linagliptin reverses WD-induced DD, possibly by targeting TRAF3IP2 expression and its downstream inflammatory signaling.