sitagliptin-phosphate and Hypoxia

With vildagliptin and sitagliptin on the market for the treatment of type 2 diabetes, dipeptidyl peptidase 4 (DPP4, EC 3.4.14.5) research has entered a new era. Scientists aim to uncover the broader pharmacological profile of DPP4 inhibitors and search for therapeutic opportunities outside diabetes. During the pre-clinical and clinical evaluation of vildagliptin and sitagliptin, there has been a growing awareness of the presence of other DPP4-like peptidases in various cells and tissues. This fuelled the development of more inhibitors with defined selectivity for DPP2, 8 and 9 that were used to investigate the expression, distribution and regulation of these peptidases. In turn, these studies increased the insights in the role of DPP4 in the body's response to various insults.

Topics: Adamantane; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Hypoxia; Neoplasms; Nitriles; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Triazoles; Vildagliptin

Potential ischemia/reperfusion (I/R) injuries are commonly induced during treatment of cardiovascular diseases, such as acute myocardial infarction (AMI). It is reported that oxidative stress and over-autophagy in cardiomyocytes are involved in the pathogenesis of I/R injury. Sitagliptin is an effective inhibitor of dipeptidyl peptidase 4 (DPP-4) for the treatment of diabetes, which is recently reported to regulate oxidative stress and autophagy. The present study is designed to explore the function of Sitagliptin on I/R injury. Hypoxia/reoxygenation (H/R) condition was used to simulate the I/R injury on cardiomyocytes. We found that the declined cell viability and elevated expression level of creatine kinase myocardial band (CK-MB) were observed in the H/R group, accompanied by the increased mitochondrial reactive oxygen species (ROS), elevated cellular malondialdehyde (MDA) level, and mitochondrial dysfunction. After Sitagliptin treatment, the damages in H9c2 cardiomyocytes, oxidative stress, and mitochondrial dysfunction were significantly alleviated. In addition, the overactivated autophagy and mitophagy in H/R-challenged cardiomyocytes were dramatically mitigated by Sitagliptin, accompanied by the upregulation of SIRT3. Lastly, the protective effect of Sitagliptin on H/R-induced mitophagy, autophagy, and damages in cardiomyocytes was dramatically abolished by the knockdown of SIRT3. Taken together, our data reveal that Sitagliptin ameliorated the H/R-induced injury in cardiomyocytes by mediating sirtuin 3 (SIRT3) and autophagy.

Topics: Autophagy; Humans; Hypoxia; Myocardial Reperfusion Injury; Myocytes, Cardiac; Sirtuin 3; Sitagliptin Phosphate