01. New Research Reveals a Novel Target for Atherosclerosis Recently, a joint research team from multiple departments of the UCLA School of Medicine published a significant study in the journalArteriosclerosis, Thrombosis, and Vascular Biology. Through genetic analysis and in vitro/in vivo experiments, the study confirmed that the nicotinamide N-methyltransferase (NNMT) gene is a key regulator of atherosclerosis. NAD metabolism plays a central role in the development of atherosclerotic lesions by regulating macrophage proliferation and apoptosis. This discovery uncovers a new link between NAD metabolism and cardiovascular health, providing new evidence and potential directions for targeted vascular support strategies. As the main pathological basis of cardiovascular conditions, atherosclerosis involves the abnormal accumulation and proliferation of macrophages in blood vessel walls, as well as foam cell formation. For a long time, identifying key molecular targets that regulate this process has been a focus of research in the cardiovascular field.
02. Understanding the NNMT Enzyme Previous studies have shown that NAD, a key intracellular coenzyme, is involved in various physiological processes such as energy metabolism and redox balance. However, its specific role and regulatory mechanisms in atherosclerosis have not been fully clarified. Using genome-wide association analysis (GWAS) in mice, the research team identified the NNMT gene on chromosome 9 as closely associated with atherosclerosis, and further explored its connection with NAD metabolism. NNMT (nicotinamide N-methyltransferase) is a metabolic enzyme widely present in the body. Its core function is to use S-adenosylmethionine (SAM) as a methyl donor to catalyze the methylation of nicotinamide (a key precursor for NAD synthesis) into N-methylnicotinamide (MNAM), thereby regulating the salvage synthesis and metabolic balance of intracellular NAD. Initially regarded as a nicotinamide-clearing enzyme, subsequent studies have found that it plays important roles in various metabolic pathways and health conditions, and is expressed in the liver, adipose tissue, macrophages, and other tissues—making it the core regulatory gene focused on in this study.
03. Mouse Experiments Validate NNMT’s Role in Atherosclerosis The research team adopted a rigorous experimental approach: "gene localization - functional verification - mechanism analysis". First, through GWAS using the Hybrid Mouse Diversity Panel (HMDP), they found that the expression level of the NNMT gene on chromosome 9 was highly correlated with atherosclerotic lesion area in more than 100 inbred mouse strains, and may be a causal gene for the condition. To verify this hypothesis, researchers used genetic methods to inhibit systemic NNMT in APOE-Leiden.CETP transgenic mice with a hyperlipidemic background. The results showed that lesion area was reduced by 10-fold in female mice and 5-fold in male mice, accompanied by decreased plasma levels of low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) cholesterol—directly confirming NNMT’s regulatory role in atherosclerosis. To identify the core tissues and cell types through which NNMT exerts its effects, the team conducted tissue-specific knockdown experiments. Although NNMT is highly expressed in the liver and adipose tissue, targeted knockdown of NNMT in these two tissues using adeno-associated virus (AAV) did not significantly improve atherosclerotic lesions in mice. Bone marrow transplantation experiments provided key clues: transplanting bone marrow from NNMT-knockout mice into irradiated recipient mice reduced atherosclerotic lesion area by 50%, and significantly decreased the proliferation ability and increased the apoptosis level of macrophages at lesion sites. Meanwhile, supplementary experiments targeting the NAD glycohydrolase CD38 showed that bone marrow transplantation from CD38-knockout mice also significantly alleviated atherosclerosis. NNMT knockout reduces the methylation of nicotinamide, allowing nicotinamide to be used by the salvage metabolic pathway to synthesize NAD. CD38 knockout reduces NAD degradation. Both pathways increase NAD availability, further confirming the core role of NAD level regulation in atherosclerosis.
04. Mechanism Analysis of NNMT’s Action In vitro cell experiments further revealed the underlying mechanism: bone marrow-derived macrophages isolated from NNMT heterozygous knockout mice had a more than 50% higher NAD/NADH ratio compared to wild-type mice, along with a 50% reduction in cell proliferation rate and a significant increase in apoptosis rate. Consistent results were obtained by inhibiting NNMT expression in macrophages using siRNA. This indicates that NNMT inhibits the salvage synthesis of NAD by consuming nicotinamide (a precursor for NAD synthesis), thereby regulating macrophage proliferation and apoptosis—when NNMT is inhibited, the conversion of nicotinamide to NAD increases, and the elevated NAD level inhibits macrophage proliferation and promotes apoptosis, thereby reducing lesion accumulation in blood vessel walls. Notably, however, intervention at the level of NAD metabolites alone (such as supplementing nicotinamide, a substrate of NNMT, or N-methylnicotinamide (MNAM), its product) could not replicate the anti-atherosclerotic effects of NNMT inhibition. In addition, the study found that the lipid-lowering effect of NNMT can only explain about 30% of its anti-atherosclerotic effect. This indicates that NNMT’s regulation of the condition is not through affecting systemic circulating NAD metabolite levels or blood lipid levels, but directly acting on macrophages at local lesion sites.
05. Medical Application Prospects of NNMT as a Target This research opens up new horizons for the application of NAD metabolism in health and wellness, especially bringing multiple potential directions for vascular health support. In terms of target development, specific inhibitors targeting macrophage NNMT may become a new generation of strategies for supporting vascular health. Unlike traditional lipid-lowering approaches, these strategies can directly target macrophages at the core of lesions by regulating intracellular NAD levels, inhibiting lesion progression from the pathological root, and are expected to provide new options for individuals with poor response to existing approaches. At the same time, as a NAD-degrading enzyme, CD38 inhibitors have shown potential in some health research. This study provides scientific support for their expansion to vascular health support, and combined strategies targeting the NAD metabolic pathway may be developed in the future. In terms of health risk prediction, single nucleotide polymorphisms (SNPs) of the NNMT gene (such as rs33700043) can explain 30%-70% of the differences in NNMT expression. Such genetic markers may be combined with plasma NAD metabolite levels in the future to serve as biomarkers for assessing individual atherosclerosis risk, helping to achieve precise prevention of cardiovascular health issues. In addition, the NAD metabolism-macrophage function regulatory axis revealed in this study also provides a reference for the research of other inflammation-related conditions, such as diabetic vascular complications and rheumatoid arthritis, which is expected to promote the wide application of NAD metabolism targets in multi-system health support. 06. Conclusion However, further exploration is needed to translate basic research results into practical health applications. Currently, studies are mainly based on mouse models, and the safety and effectiveness of NNMT inhibition in humans still need to be verified through more research. At the same time, the specific molecular mechanisms by which NAD level regulation in macrophages controls cell proliferation and apoptosis—such as interactions with the Akt signaling pathway and the SIRT1-FOXO3 signaling axis—still require in-depth analysis. In addition, how to achieve specific delivery of NNMT inhibitors to macrophages, avoiding effects on other tissues such as the liver and adipose tissue, is also a technical challenge that needs to be addressed in the future. Overall, this study from the UCLA team is the first to clarify the core regulatory role of the NNMT-NAD metabolism-macrophage axis in atherosclerosis, providing a new perspective for the research on the pathological mechanisms of cardiovascular health. With further analysis of the NAD metabolism regulatory network and the advancement of related targeted strategies, it is expected to bring breakthroughs in the support and prevention of atherosclerosis in the near future, making NAD metabolism, a classic intracellular pathway, a new line of defense for protecting vascular health.
References Sinha S K, Swichkow C R, Farahi L, et al. NAD metabolism regulates proliferation of macrophages in atherosclerosis[J]. Arteriosclerosis, thrombosis, and vascular biology, 2025, 45(11): 1997-2014.
