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

Abstract

BackgroundDiastolic 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.MethodsFemale C56Bl/6 J mice were fed an obesogenic WD high in fat and simple sugars, and supplemented or not with linagliptin for 16 weeks.ResultsWD 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.ConclusionsTogether, 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.

The role of renal dipeptidyl peptidase-4 in kidney disease: renal effects of dipeptidyl peptidase-4 inhibitors with a focus on linagliptin

“…As described above, linagliptin ameliorated kidney fibrosis (both tubulointerstitial fibrosis and glomerulosclerosis) and albuminuria in a murine model of type 1 diabetes without altering blood glucose levels [64]. This is consistent with studies showing antifibrotic effects of linagliptin in the heart [80][81][82][83], aorta [84] and peritoneum [85] in animal models. The antifibrotic changes in the kidneys occurred together with inhibition of the endothelial-to-mesenchymal transition (EndMT) [64], which is thought to be an important source of kidney fibroblasts [86][87][88][89] that play a key role in renal fibrosis [90].…”

Plasma CXCL1 levels and TRAF3IP2 variants in patients with myocardial infarction

“…Previous studies have shown that western diet increases the expression of TRAF3IP2 in mice and male transgenic mice with cardiomyocyte‐specific TRAF3IP2 overexpression develop spontaneous myocardial hypertrophy, fibrosis, and dysfunction where a gender‐dependent effect of TRAF3IP2 is suggested . In addition, dipeptidyl peptidase‐4 inhibition results in simultaneous reduction of TRAF3IP2, proinflammatory cytokine, and growth factor expression, as well as collagen induction in primary cardiac fibroblasts . This phenomenon which reverses diastolic dysfunction through targeting TRAF3IP2 expression and its downstream inflammatory signaling has cardioprotective effects …”

“…The incidence of these three mechanical effects is very low, but is associated with very poor prognosis . Previous studies have shown that western diet increases the expression of TRAF3IP2 in mice and male transgenic mice with cardiomyocyte‐specific TRAF3IP2 overexpression develop spontaneous myocardial hypertrophy, fibrosis, and dysfunction where a gender‐dependent effect of TRAF3IP2 is suggested . In addition, dipeptidyl peptidase‐4 inhibition results in simultaneous reduction of TRAF3IP2, proinflammatory cytokine, and growth factor expression, as well as collagen induction in primary cardiac fibroblasts .…”

“…30 In addition, dipeptidyl peptidase-4 inhibition results in simultaneous reduction of TRAF3IP2, proinflammatory cytokine, and growth factor expression, as well as collagen induction in primary cardiac fibroblasts. 29 This phenomenon which reverses diastolic dysfunction through targeting TRAF3IP2 expression and its downstream inflammatory signaling has cardioprotective effects. 29 We observed an increase in the mutant/risk allele of TRAF3IP2 (rs33980500) in MI patients with anterolateral hypokinesia.…”

“…29 This phenomenon which reverses diastolic dysfunction through targeting TRAF3IP2 expression and its downstream inflammatory signaling has cardioprotective effects. 29 We observed an increase in the mutant/risk allele of TRAF3IP2 (rs33980500) in MI patients with anterolateral hypokinesia.…”