NNMT modulates macrophage polarization and atherosclerosis through AMPKα and HIF1α pathways

Macrophage polarization and inflammatory responses play a pivotal role throughout all stages of atherosclerosis. Wedelolactone (WDL), a naturally occurring coumestan derivative, exhibits potent inhibitory activity against nicotinamide N-methyltransferase (NNMT). This study aims to clarify the role of NNMT in macrophage polarization and explore the anti-atherosclerotic effects of WDL together with its molecular mechanisms linked to NNMT inhibition.

Immunofluorescent staining was performed on high-fat-diet (HFD) fed apoE-deficient (apoE^-/-) mice to localize NNMT and determine its abundance within atherosclerotic lesions. In cultured macrophages, expression levels of polarization markers and NNMT were examined following transfection with/without NNMTsiRNA and/or intervention with WDL. In vivo, HFD-fed apoE^-/- mice were treated with WDL, and atherosclerotic lesions were comprehensively assessed using ultrasound imaging, histological staining, and immunological labeling.

NNMT expression was markedly elevated in macrophages of atherosclerotic plaques, and its abundance correlated tightly with macrophage polarization status. Accordingly, WDL remodels macrophage polarization to M2 phenotype through activating AMPKα and depressing HIF1α pathway in an NNMT-dependent manner. Thereby, WDL significantly alleviated atherosclerosis in apoE^-/- mice.

The results demonstrate that NNMT modulates macrophage polarization and its inhibition with WDL alleviates atherosclerosis, which delineates the functional cascade connecting NNMT suppression with macrophage phenotypic remodeling, and offers novel therapeutic strategies for clinical atherosclerosis management.