ADMA: A Key Player in the Relationship between Vascular Dysfunction and Inflammation in Atherosclerosis

Figure 1. Asymmetric dimethylarginine increases endothelial activation. At the site of atherosclerotic lesions, inflammation leads to endothelial activation, reducing endothelial barrier integrity, enhancing the expression of adhesion molecules and increasing endothelial production of inflammatory markers. Asymmetric dimethylarginine (ADMA) treatment of endothelial cell monolayers increased endothelial permeability, increasing oxLDL transmigration. Actin cytoskeleton remodelling and reactive oxygen species (ROS) production, which are both induced by ADMA treatment, lead to the upregulation of ERK and NF-kB signalling and increased cytokine production. ADMA treatment also increases the expression of adhesion molecules ICAM and VCAM, leading to increased monocyte adhesiveness. Abbreviations: ADMA—asymmetric dimethylarginine, oxLDL—oxidised low-density lipoprotein, ROS—reactive oxygen species, ERK—extracellular signal related kinase, NF-kB—nuclear factor kappa-light-chain enhancer of activated B cells, ICAM—intracellular adhesion molecule, VCAM—vascular cell adhesion protein, MCP-1—monocyte chemoattractant protein 1, TNF α—tumour necrosis factor alpha, IL8—interleukin 8.

Figure 2. ADMA increases the generation of foam cells. Macrophages play a key role in scavenging oxidized lipids within the vessel wall; however, in atherosclerotic plaques, excessive lipid accumulation leads to the formation of foam cells. Macrophages express scavenger receptors, including lectin-like, oxidized, lipoprotein receptor-1 (LOX-1), which mediate the uptake of oxidized LDL (oxLDL). Once within the macrophage, oxLDL is taken up by the lysosome and converted to free cholesterol. Acetyl coenzyme A: cholesterol aceyltransferase-1 (ACAT) esterifies the cholesterol to be stored within the endoplasmic reticulum. Asymmetric dimethylarginine (ADMA) treatment of macrophages upregulates LOX-1 and ACAT-1, increasing cholesterol storage. ADMA also downregulates the expression of key ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, thereby reducing cholesterol efflux from the macrophage and contributing to foam cell formation.