Teneligliptin mitigates diabetic cardiomyopathy by inhibiting activation of the NLRP3 inflammasome

Abstract

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.

AIM

To examine the therapeutic effects of teneligliptin on DCM in diabetic mice.

METHODS

Streptozotocin was administered to induce diabetes in mice, followed by treatment with 30 mg/kg teneligliptin.

RESULTS

Marked increases in cardiomyocyte area and cardiac hypertrophy indicator heart weight/tibia length reductions in fractional shortening, ejection fraction, and heart rate; increases in creatine kinase-MB (CK-MB), aspartate transaminase (AST), and lactate dehydrogenase (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 interleukin-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. 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.

CONCLUSION

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

Keywords: Diabetic cardiomyopathy, Teneligliptin, NLRP3, AMPK, Interleukin-1β

Core Tip: Teneligliptin mitigated diabetic cardiomyopathy by mitigating the activation of NLRP3 (NOD-like receptor protein 3) inflammasome. Teneligliptin reversal markedly increased cardiomyocyte area and heart weight/tibia length, reduced fractional shortening, ejection fraction, and heart rate, increased creatine kinase-MB (CK-MB), aspartate transaminase (AST), and lactate dehydrogenase (LDH) levels, and upregulated NADPH oxidase 4 in streptozotocin-induced diabetic mice. Teneligliptin repressed activated NLRP3 inflammasome and increased CK-MB, AST, and LDH levels in glucose-stimulated cardiomyocytes, accompanied by an upregulation of phosphorylated-adenosine 5‘-monophosphate and activated protein kinase.