New UCLA Research Identifies NAD Metabolism as Atherosclerosis Regulatory Target
A joint research team from multiple departments of the UCLA School of Medicine published a landmark study in the journal Arteriosclerosis, Thrombosis, and Vascular Biology. Through rigorous genetic analysis and integrated in vitro and in vivo experiments, the study confirmed that the nicotinamide N-methyltransferase (NNMT) gene acts as a core regulator of atherosclerosis. Cellular metabolic balance dominates the development of atherosclerotic lesions by modulating macrophage proliferation and apoptosis. This pioneering discovery bridges the research gap between cellular metabolic regulation and cardiovascular health, providing novel scientific evidence and targeted intervention directions for vascular protection.
As the primary pathological basis of various cardiovascular disorders, atherosclerosis is characterized by abnormal macrophage accumulation, excessive cell proliferation on vascular walls, and foam cell formation. For decades, exploring key molecular targets to inhibit this pathological process has been the core focus of cardiovascular research, and the newly revealedNAD metabolism regulatory axis fills an important technical blank in this field.
Core Function of NNMT Enzyme: Key Regulator of NAD Metabolism
As a vital intracellular coenzyme, NAD participates in multiple physiological activities including energy metabolism and redox balance. However, its specific regulatory mechanism in atherosclerosis remained unclear for a long time. Using genome-wide association analysis (GWAS) on mouse models, the UCLA research team successfully localized the NNMT gene on chromosome 9, verifying its strong correlation with atherosclerotic lesions and its decisive regulatory effect on NAD metabolism.
Nicotinamide N-methyltransferase (NNMT) is a widely distributed metabolic enzyme in human tissues. Its core function is to catalyze the methylation of nicotinamide — an essential precursor for NAD synthesis — into N-methylnicotinamide (MNAM), with S-adenosylmethionine (SAM) as the methyl donor. This process directly modulates the salvage synthesis pathway and dynamic balance of intracellular coenzyme levels. Initially defined as a nicotinamide clearance enzyme, NNMT has now been proven to participate in multiple metabolic pathways. It is highly expressed in the liver, adipose tissue, and macrophages, making it the core upstream gene controlling vascular lesion progression.
Mouse Model Experiments Verify NNMT-NAD Metabolism Regulatory Axis
The research team adopted a rigorous three-stage experimental framework: gene localization, functional verification, and mechanism analysis. Based on the Hybrid Mouse Diversity Panel (HMDP) GWAS analysis of over 100 inbred mouse strains, researchers confirmed that NNMT gene expression level is highly positively correlated with atherosclerotic lesion area, proving its causal relationship with vascular lesions.
In subsequent functional verification experiments on hyperlipidemic APOE-Leiden.CETP transgenic mice, systemic NNMT inhibition achieved remarkable vascular protection effects: the atherosclerotic lesion area was reduced by 10-fold in female mice and 5-fold in male mice. Meanwhile, plasma low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) cholesterol levels decreased significantly, directly confirming that NNMT mediates atherosclerosis progression by disrupting intracellular metabolic homeostasis.
Tissue-specific knockdown experiments further clarified the core action site of this mechanism. Although NNMT is highly expressed in the liver and adipose tissue, targeted NNMT inhibition in these tissues failed to improve atherosclerotic lesions. In contrast, bone marrow transplantation experiments delivered decisive results: transplanting bone marrow from NNMT-knockout mice reduced lesion area by 50%, significantly inhibited macrophage proliferation, and promoted macrophage apoptosis at lesion sites.
Supplementary experiments targeting CD38, a key NAD glycohydrolase, further verified the core status of cellular metabolic balance. CD38 knockout also effectively alleviated atherosclerosis. Mechanistically, NNMT knockout reduces nicotinamide methylation, reserving more precursors for NAD salvage synthesis; CD38 knockout decreases NAD degradation. Both interventions elevate intracellular NAD availability, jointly confirming that balanced coenzyme metabolism is the key to suppressing vascular lesions.
Molecular Mechanism: How NAD Metabolism Modulates Macrophage and Vascular Health
In vitro cell experiments further revealed the underlying molecular logic of the NNMT-metabolism-macrophage regulatory axis. Bone marrow-derived macrophages from NNMT heterozygous knockout mice exhibited a more than 50% higher NAD/NADH ratio than wild-type mice. The elevated coenzyme balance reduced macrophage proliferation rate by 50% and markedly enhanced cell apoptosis. Consistent results were observed after inhibiting NNMT expression via siRNA intervention.
Specifically, NNMT consumes NAD synthesis precursors to block intracellular NAD salvage synthesis, lowering NAD levels to trigger excessive macrophage proliferation and lesion accumulation. When NNMT is inhibited, unconsumed nicotinamide fully participates in NAD synthesis, elevating intracellular NAD levels to suppress macrophage overgrowth, promote pathological cell apoptosis, and ultimately reduce atherosclerotic lesion deposition on vascular walls.
Notably, single intervention of NAD metabolites cannot replicate the anti-atherosclerotic effect of NNMT inhibition. Additionally, the lipid-lowering effect of NNMT regulation only accounts for 30% of its vascular protection benefits. This proves that NNMT improves atherosclerosis not by regulating systemic blood lipids or circulating NAD metabolites, but by locally modulating cellular metabolism in lesion macrophages to reverse pathological changes.
Clinical and Wellness Application Prospects of NAD Metabolism Targets
This groundbreaking study expands the application boundary of coenzyme metabolism research and brings multiple innovative directions for vascular health maintenance and atherosclerosis intervention. In terms of targeted therapy, macrophage-specific NNMT inhibitors represent a new generation of vascular protection strategies. Different from traditional lipid-lowering methods, this approach targets the core pathological macrophages, regulates local cellular metabolic balance to block lesion progression from the root, and provides an alternative solution for groups with poor response to conventional interventions.
As a classic NAD-degrading enzyme, CD38 inhibitors have been widely studied in metabolic regulation. This research provides solid scientific support for their expanded application in vascular health. In the future, combined intervention strategies targeting the entire NAD metabolism pathway are expected to achieve better comprehensive vascular protection effects.
In terms of health risk prediction, NNMT gene single nucleotide polymorphisms (SNPs) such as rs33700043 can explain 30% to 70% of individual differences in NNMT expression. Combined with plasma NAD metabolite detection, these genetic markers can be developed as biomarkers for atherosclerosis risk assessment, realizing precise early warning and targeted prevention of cardiovascular risks based on cellular metabolic status.
Furthermore, the newly discovered metabolism-macrophage regulatory axis provides valuable references for researching inflammation-related complications, including diabetic vascular lesions and rheumatoid arthritis, promoting the wide application of NAD metabolic targets in multi-system health management.
Research Limitations and Future Development of NAD Metabolism Intervention
Despite the promising prospects, the translational application of NAD metabolic regulation and NNMT targeted intervention still requires further in-depth research. Current experimental conclusions are mainly based on mouse models, and human clinical safety and efficacy data remain to be supplemented and verified.
In addition, the downstream molecular mechanisms by which macrophage NAD metabolism regulates cell proliferation and apoptosis are not fully clarified. The interaction between NAD levels and key signaling pathways including the Akt pathway and SIRT1-FOXO3 axis still needs systematic exploration. Technically, achieving precise targeted delivery of NNMT inhibitors to macrophages while avoiding adverse effects on the liver and adipose tissue is also a key challenge to be solved for clinical transformation.
Conclusion
This UCLA study is the first to systematically clarify the core regulatory role of the NNMT-NAD metabolism-macrophage axis in atherosclerosis, opening a new research perspective for cardiovascular pathological mechanisms and vascular health intervention. With continuous in-depth research on the NAD metabolic regulatory network and the iteration of targeted intervention technologies, NAD metabolic pathways are expected to become a new core defense line for preventing and improving atherosclerosis, bringing innovative breakthroughs in precise cardiovascular health management.
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.
