Ginsenoside Rb1 mitigates atherosclerosis in part through modulating FTO-mediated m6A RNA modification in NETs-induced endothelial activation

Background Ginsenoside Rb1 (Rb1) exerts pharmacological effects in attenuating the progression of atherosclerosis. However, whether the anti-atherosclerotic effects of Rb1 involve suppressing neutrophil extracellular traps (NETs)-induced endothelial activation and whether N 6 -methyadenosine (m 6 A) RNA modification is mechanistically implicated in this process remain unknown. Methods High fat diet (HFD)-fed Apoe −/− mice were subjected to histological, immunohistological and molecular biological analyses. Moreover, NETs-induced endothelial activation and m 6 A RNA methylation were assessed in human aortic endothelial cells (HAECs). Results Rb1 mitigated atherosclerotic lesions and endothelial activation in vivo . Rb1 diminished adhesion of neutrophils and monocytes to NETs-stimulated HAECs, offset NETs-upregulated endothelial expression of ICAM1 , VCAM1 , SELE and SELP , and counteracted NETs-induced endothelial barrier impairment in vitro . NETs exposure significantly decreased the level of m 6 A RNA methylation and increased the expression of demethylase fat mass and obesity-associated protein (FTO) in HAECs, whereas Rb1 treatment enhanced m 6 A RNA methylation and reduced FTO expression in the NETs-stimulated HAECs. Overexpression of FTO abrogated the protective effects of Rb1 against NETs-induced endothelial activation in HAECs. Furthermore, Fto overexpression in endothelial cells partially abolished Rb1-confered attenuation of atherosclerotic pathologies and the aortic expression of Vcam1 in HFD-fed Apoe −/− mice. Conclusion The work here demonstrates that Rb1 mitigates atherosclerosis in part by suppressing NETs-induced endothelial activation. Mechanistically, the pharmacological effects of Rb1 in attenuating NETs-induced endothelial activation are in part mediated by modulating FTO-mediated m 6 A RNA demethylation in endothelial cells.

Abstract licence: CC BY

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