AMPK Activation and Atherosclerosis Modulation

AMP-activated protein kinase (AMPK) serves as a central metabolic regulator, integrating signals of cellular energy status to orchestrate lipid handling, inflammatory responses and vascular cell behaviour. In the context of atherosclerosis, AMPK activation influences multiple processes: it enhances cholesterol efflux from macrophage foam cells, attenuates de novo lipogenesis, promotes autophagy and directs macrophage polarisation towards a resolving phenotype. These combined effects reduce lipid accumulation, dampen chronic inflammation within the arterial wall and limit plaque progression. Beyond macrophages, AMPK activity in endothelial cells and vascular smooth muscle cells modulates barrier function, inhibits cell migration and supports plaque stability. Collectively, pharmacological or physiological triggers of AMPK represent promising avenues to curb atherogenesis and its clinical sequelae.

Research from Nature Portfolio

A foundational investigation demonstrated that co-administration of metformin with atorvastatin in a rabbit model of high-cholesterol diet markedly reduced atherosclerotic lesion area without further lowering plasma lipids. This combination therapy shifted high-density lipoprotein (HDL) composition towards larger, more functional subfractions and enhanced macrophage cholesterol efflux through upregulation of ATP-binding cassette transporters ABCA1 and ABCG1. In vitro studies confirmed synergistic promotion of cholesterol removal and transporter expression in cultured macrophages. These findings underscore the translational potential of coupling AMPK-activating agents with lipid-lowering drugs to reinforce anti-atherogenic mechanisms.

Research from all publishers

Recent work with PF-06409577, a highly selective activator of macrophage AMPKβ1 complexes, revealed dose-dependent phosphorylation of downstream substrates such as ULK1 and ACC, thereby stimulating autophagy and fatty acid oxidation while suppressing cholesterol synthesis and inflammatory gene expression. In two mouse models, treatment led to significant reductions in atherosclerotic plaque burden in a myeloid AMPKβ1-dependent manner. Meanwhile, a comprehensive review of the calcium/calmodulin-dependent kinase-like (CaMKL) family highlighted the LKB1–AMPK axis as a master kinase pathway conferring atheroprotective effects, in contrast to downstream MARK subfamily kinases implicated in lesion exacerbation. Together, these studies illustrate both the promise of targeted AMPK-β1 activation and the value of mapping upstream kinase networks to refine therapeutic strategies.

AMPK Activation and Atherosclerosis Modulation publication trend

The graph below shows the total number of articles in ampk activation and atherosclerosis modulation across all publications each year (not limited to Nature Index journals).

Technical terms

AMPK: A serine/threonine kinase that senses cellular energy depletion and phosphorylates metabolic and transcriptional regulators to restore homeostasis.

Foam cell: A macrophage engorged with lipid droplets, formed upon uptake of modified low-density lipoprotein, and central to plaque development.

Autophagy: A catabolic process degrading cytoplasmic constituents via lysosomes, facilitating lipid clearance and limiting inflammation in vascular cells.

Reverse cholesterol transport: The pathway by which excess cholesterol is effluxed from peripheral cells to HDL particles and delivered to the liver for excretion.

Macrophage polarisation: The functional adaptation of macrophages into pro-inflammatory (M1) or pro-resolving (M2) states, influencing plaque stability and regression.

References

1. Combined use of metformin and atorvastatin attenuates atherosclerosis in rabbits fed a high-cholesterol diet. Scientific Reports (2017).
2. Macrophage AMPK β1 activation by PF-06409577 reduces the inflammatory response, cholesterol synthesis, and atherosclerosis in mice. iScience (2023).
3. Navigating the Maze of Kinases: CaMK-like Family Protein Kinases and Their Role in Atherosclerosis. International Journal of Molecular Sciences (2024).