Kakonein restores diabetes‐induced endothelial junction dysfunction via promoting autophagy‐mediated NLRP3 inflammasome degradation

Abstract

In diabetes‐induced complications, inflammatory‐mediated endothelial dysfunction is the core of disease progression. Evidence shows that kakonein, an isoflavone common in Pueraria, can effectively treat diabetes and its complications. Therefore, we explored whether kakonein protects cardiovascular endothelial function by inhibiting inflammatory responses. In this study, C57BL/6J mice were injected with streptozocin to establish a diabetes model and treated with kakonein or metformin for 7 days. The protective effect of kakonein on cardiovascular endothelial junctions and NLRP3 inflammasome activation was verified through immunofluorescence and ELISA assay. In addition, the regulation of autophagy on the NLRP3 inflammasome was investigated through Western blot, immunofluorescence and RT‐qPCR. Results showed that kakonein restored the function of endothelial junctions and inhibited the assembly and activation of the NLRP3 inflammasome. Interestingly, kakonein decreased the expression of NLRP3 inflammasome protein by not reducing the transcriptional levels of NLRP3 and caspase‐1. Kakonein activated autophagy in an AMPK‐dependent manner, which reduced the activation of the NLRP3 inflammasome. In addition, kakonein inhibited both hyperglycaemia‐induced cardiovascular endothelial junction dysfunction and NLRP3 inflammasome activation, similar to autophagy agonist. Our findings indicated that kakonein exerts a protective effect on hyperglycaemia‐induced chronic vascular disease by regulating the NLRP3 inflammasome through autophagy.

Inhibitors of the NLRP3 inflammasome pathway as promising therapeutic candidates for inflammatory diseases (Review)

“…Additionally, there is evidence to indicate that hyperglycemic conditions cause endothelial cell dysfunction and NLRP3 inflammasome activation ( 75 ). MCC950, an NLRP3 inhibitor ( 11 ), tetramethylpyrazine ( 76 ), hydrogen sulfide ( 77 ) and Kakonein ( 78 ) have been shown to improve endothelial dysfunction by suppressing NLRP3 inflammasome activation or the production of its effectors, caspase-1 and IL-1β. Moreover, MCC950 targets NLRP3-mediated inflammation, and reduces plaque development, promotes plaque stability and improves diabetes-associated vascular disease ( 79 ).…”

Physiological and pathological characteristics of vascular endothelial injury in diabetes and the regulatory mechanism of autophagy

“…In addition, lysosomal damage mediates the activation of the inflammasome-NLR family pyrin domain containing 3 (NLRP3) and the release of high mobility cassette protein 1, leading to endothelial hyperpermeability. However, activating autophagy via the AMPK pathway can inhibit the assembly and activation of NLRP3, restore endothelial connectivity, and reduce endothelial permeability (97,98). Finally, Weikel KA et al found an increase in glycogen synthase kinase 3b (GSK3b) activity in DM patients and animals participating in autophagy inhibition.…”

Pharmacological Activity, Pharmacokinetics, and Clinical Research Progress of Puerarin

“…Autophagy is deemed to be an efficient regulator of NLRP3 inflammasome activation in hyperglycemia-related vascular complications. Puerarin regulates NLRP3 inflammation through autophagy and has protective effects on chronic vascular diseases induced by hyperglycemia [ 102 ]. Inflammation-mediated endothelial dysfunction takes a pivotal effect in cardiovascular disease caused by diabetes.…”