Sitagliptin decreases ventricular arrhythmias by attenuated glucose-dependent insulinotropic polypeptide (GIP)-dependent resistin signalling in infarcted rats

Abstract

SynopsisMyocardial infarction (MI) was associated with insulin resistance, in which resistin acts as a critical mediator. We aimed to determine whether sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, can attenuate arrhythmias by regulating resistin-dependent nerve growth factor (NGF) expression in postinfarcted rats. Normoglycaemic male Wistar rats after ligating coronary artery were randomized to either vehicle or sitagliptin for 4 weeks starting 24 h after operation. Post-infarction was associated with increased myocardial noradrenaline [norepinephrine (NE)] levels and sympathetic hyperinnervation. Compared with vehicle, sympathetic innervation was blunted after administering sitagliptin, as assessed by immunofluorescent analysis of tyrosine hydroxylase, growth-associated factor 43 and neurofilament and western blotting and real-time quantitative RT-PCR of NGF. Arrhythmic scores in the sitagliptintreated infarcted rats were significantly lower than those in vehicle. Furthermore, sitagliptin was associated with reduced resistin expression and increased Akt activity. Ex vivo studies showed that glucose-dependent insulinotropic polypeptide (GIP) infusion, but not glucagon-like peptide-1 (GLP-1), produced similar reduction in resistin levels to sitagliptin in postinfarcted rats. Furthermore, the attenuated effects of sitagliptin on NGF levels can be reversed by wortmannin (a phosphatidylinositol 3-kinase antagonist) and exogenous resistin infusion. Sitagliptin protects ventricular arrhythmias by attenuating sympathetic innervation in the non-diabetic infarcted rats. Sitagliptin attenuated resistin expression via the GIP-dependent pathway, which inhibited sympathetic innervation through a signalling pathway involving phosphatidylinositol 3-kinase (PI3K) and Akt protein.

Sitagliptin protects diabetic rats with acute myocardial infarction through induction of angiogenesis: role of IGF-1 and VEGF

“…The current study showed that in a dose-dependent manner, treatment with sitagliptin significantly improved the ECG findings, histopathological abnormalities, cardiac enzymes and body mass index changes. The present results confirm previous results that sitagliptin alleviated myocardial remodeling of the LV and improved cardiac dysfunction in diabetic rats (Liu et al, 2015), as well as it could protect against ventricular arrhythmia (T.-M. Lee, Chen, & Chang, 2016).…”

GIP as a Potential Therapeutic Target for Atherosclerotic Cardiovascular Disease–A Systematic Review

“…Indeed, infusion of active GIP (25 nmol/kg/day) for 4 weeks suppressed the left ventricle cardiomyocyte enlargement and interstitial fibrosis, which were associated with concomitant reductions in cell apoptosis and transforming growth factor-β protein expression in the hearts of angiotensin II-infused ApoE-/mice [25]. In other studies, effects of GLP-1 on infarcted rat hearts were evaluated [99,[107][108][109]. In the infarcted rat hearts induced by coronary artery ligation, perfusion with GIP, but not GLP-1 at the infusion rate at 100 nmol/l for 1 h reduced the protein expression levels of resistin [107], a promoter of cardiac remodeling and dysfunction [108,109].…”

“…In other studies, effects of GLP-1 on infarcted rat hearts were evaluated [99,[107][108][109]. In the infarcted rat hearts induced by coronary artery ligation, perfusion with GIP, but not GLP-1 at the infusion rate at 100 nmol/l for 1 h reduced the protein expression levels of resistin [107], a promoter of cardiac remodeling and dysfunction [108,109]. In contrast to the findings, deleterious effects of GIP on cardiac remodeling were also reported in mouse models of myocardial infarction (Table 2) [99].…”

Cardiovascular effects of sitagliptin – An anti‐diabetes medicine

“…When administered with I/R surgery, mice with sitagliptin treatment showed better LV function and smaller infarct size . The cardiac infarction‐induced ventricular arrhythmia could be restored by sitagliptin, mainly contributed through decreased sympathetic innervations, increased interstitial adenosine level and resistin pathway regulation . In addition, renal ischaemic/reperfusion‐induced remote myocardium injuries could be reversed by sitagliptin treatment …”

“…The PI3K/Akt pathway promotion was also found in infarcted hearts with sitagliptin treatment. However, this effect was GIP‐dependent rather than GLP‐1‐dependent as demonstrated, since the GIP administration alone showed similar effects with sitagliptin . Notably, nitric oxide (NO) plays a vital role in maintaining physiological cardiovascular function.…”