Teneligliptin mitigates diabetic cardiomyopathy by inhibiting activation of the NLRP3 inflammasome

ARTICLE HIGHLIGHTS

Research background

Diabetic cardiomyopathy (DCM), which is a complication of diabetes, poses a great threat to public health. Recent studies have confirmed the role of NLRP3 (NOD-like receptor protein 3) activation in DCM development through the inflammatory response. Teneligliptin is an oral hypoglycemic dipeptidyl peptidase-IV inhibitor used to treat diabetes. Teneligliptin has recently been reported to have anti-inflammatory and protective effects on myocardial cells.

Research motivation

This study examined the therapeutic effects of teneligliptin on DCM in diabetic mice.

Research objectives

Teneligliptin improves DCM by means of NLRP3, providing a new target for teneligliptin in the treatment of DCM.

Research methods

Streptozotocin (STZ) was administered to induce diabetes in mice, followed by treatment with 30 mg/kg teneligliptin. Small animal ultrasonic apparatus was used to measure mice heart function, The levels of creatine kinase-MB (CK-MB), aspartate transaminase (AST), lactate dehydrogenase (LDH), and interleukin (IL)-1β were detected by ELISA, cardiomyocytes areas were measured by HE staining, Real-time PCR was used to measure NOX-4 mRNA expression, western blot was used to measure NOX-4, NLRP3, caspase-1, AMPK, p-AMPK protein expression level, primary cardiomyocytes was isolated in neonatal mice. The data are presented as the mean ± SD and were analyzed using one-way analysis of variance with GraphPad Prism software 6.0. P < 0.05 was considered to indicate a statistically significant difference.

Research results

Marked increases in cardiomyocyte area and heart weight/tibia length; reductions in fractional shortening, ejection fraction, and heart rate; increases in CK-MB, AST, and LDH levels; and upregulated NADPH oxidase 4 were observed in diabetic mice, all of which were significantly reversed by teneligliptin. Moreover, NLRP3 inflammasome activation and increased release of IL-1β in diabetic mice were inhibited by teneligliptin. Primary mouse cardiomyocytes were treated with high glucose (30 mmol/L) with or without teneligliptin (2.5 or 5 µM) for 24 h. NLRP3 inflammasome activation and the increases in CK-MB, AST, and LDH levels in glucose-stimulated cardiomyocytes were markedly inhibited by teneligliptin, and AMP (p-adenosine 5‘-monophosphate)-p-AMPK (activated protein kinase) levels were increased. Furthermore, the beneficial effects of teneligliptin on hyperglycaemia-induced cardiomyocytes were abolished by the AMPK signaling inhibitor compound C.

Research conclusions

Overall, teneligliptin mitigated DCM by mitigating activation of the NLRP3 inflammasome.

Research perspectives

Our study suggests that in future clinical work, teneligliptin may treat diseases involving the NLRP3 pathway.