Sitagliptin attenuates cardiomyopathy by modulating the JAK/STAT signaling pathway in experimental diabetic rats

Abstract

Sitagliptin, a dipeptidyl peptidase-4 inhibitor, has been reported to promote cardioprotection in diabetic hearts by limiting hyperglycemia and hyperlipidemia. However, little is known about the involvement of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway modulation in the cardioprotective effects of sitagliptin. The current study aimed to investigate the protective effects of sitagliptin against diabetic cardiomyopathy (DCM), focusing on the modulation of the JAK/STAT pathway. Diabetes was induced by streptozotocin injection, and rats received sitagliptin orally and daily for 90 days. Diabetic rats exhibited hyperglycemia, hyperlipidemia, and a significant increase in heart-to-body weight (HW/BW) ratio. Serum troponin I and creatine kinase MB, cardiac interleukin-6 (IL-6), lipid peroxidation, and nitric oxide levels showed significant increase in diabetic rats. In contrast, both enzymatic and nonenzymatic antioxidant defenses were significantly declined in the heart of diabetic rats. Histopathological study revealed degenerations, increased collagen deposition in the heart of diabetic rats. Sitagliptin alleviated hyperglycemia, hyperlipidemia, HW/BW ratio, histological architecture, oxidative stress, and inflammation, and rejuvenated the antioxidant defenses. In addition, cardiac levels of pJAK2 and pSTAT3 were increased in diabetic rats, an effect which was remarkably decreased after sitagliptin treatment. In conclusion, these results confer an evidence that sitagliptin has great therapeutic potential on DCM through down-regulation of the JAK/STAT signaling pathway.

Simvastatin Ameliorates Diabetic Cardiomyopathy by Attenuating Oxidative Stress and Inflammation in Rats

“…Here, diabetic rats exhibited cardiac hypertrophy evidenced by the increased HW/BW ratio. Similar findings have been reported in our recent study [ 32 ]. In our study, cardiac hypertrophy was associated with increased TNF- α and cardiac NF- κ B expression.…”

“…The principal approach to control DM is lowering blood glucose levels. Here, STZ-induced diabetic rats exhibited a significant increase in blood glucose levels with concomitantly declined body weight as we previously reported [ 32 ]. Treatment with simvastatin significantly improved blood glucose levels in diabetic rats.…”

“…Additionally, statins have been proven to inhibit the activity of dipeptidyl peptidase IV (DPP-IV) [ 36 ]. In the same context, we have recently reported attenuated hyperglycemia and DCM in diabetic rats treated with the DPP-IV inhibitor sitagliptin [ 32 ]. The improved glycemic status following simvastatin treatment may have contributed to the alleviated body weight.…”

Cardiovascular effects of sitagliptin – An anti‐diabetes medicine

“…Other inflammatory factors, including TNF‐α, IL‐6 and CCL2 were decreased after sitagliptin treatment as some researchers demonstrated, which played an important role in protecting cardiac function . In an experimental diabetic model, the cardiomyopathy was attenuated via the down‐regulated JAK/STAT pathway by sitagliptin, which might induce the anti‐inflammatory effects . As reported in an experimental model, at the onset and during the progression of heart failure, the vicious cycle of DPP‐4 activity and inflammation was observed.…”

Type 2 diabetes mellitus in elderly patients treated with endocrinologists in clinical practice

“…было показано, что терапия ситаглиптином у пациентов с СД2 и острым коронарным синдромом сопровождалась снижением риска повторного инфаркта, отека легких и острой почечной недостаточности [46]. Также в эксперименте на животных моделях продемонстрировано уменьшение проявлений диабетической кардиомиопатии [47].…”