Protective Effects of Methotrexate against Proatherosclerotic Cytokines: A Review of the Evidence

Table 2

Effects of methotrexate, adenosine, AICAR, and AMPK activation on endothelial function and vascular homeostasis.

Mediator	Reported effects
Methotrexate	Release of soluble TNF-α receptor p75 ↑
	TNF-α expression/concentrations ↓
	IL-6 expression/concentrations ↓
	ICAM-1 expression ↓
	VCAM-1 expression ↓
	eNOS activity ↑
	Endothelium-dependent vasodilatation ↑
	Mitochondrial mass, membrane potential, and intracellular ATP concentrations ↑
Adenosine	TNF-α expression/concentrations ↓
	IL-6 expression/concentrations ↓
	ICAM-1 expression ↓
	VCAM-1 expression ↓
	E-selectin expression ↓
	eNOS activity ↑
	Blood pressure ↓
	Mitochondrial mass, membrane potential, and intracellular ATP concentrations ↑
	Formation of atherosclerotic lesions ↓
	Cholesterol concentrations ↓
	Triglyceride concentrations ↓
AICAR/AMPK	IL-1 expression/concentrations ↓
	IL-6 expression/concentrations ↓
	ICAM-1 expression ↓
	VCAM-1 expression ↓
	NO synthesis ↑
	Endothelium-dependent vasodilation ↑
	Endothelium-independent vasodilation ↑
	Blood pressure ↓
	Oxidative stress ↓
	Endoplasmic reticulum stress ↓
	Manganese superoxide dismutase induction ↑
	NF-κB ↓
	Monocyte adhesion to endothelial cells ↓
	Restenosis ↓
	Cholesterol efflux capacity ↑
	Cellular glucose uptake ↑
	Glycolysis ↑

AICAR: aminoimidazole carboxamide ribonucleotide; AMPK: 5 adenosine monophosphate-activated protein kinase; TNF-α: tumour necrosis factor-alpha; IL-1: interleukin-1; IL-6: interleukin-6; ICAM-1: intercellular adhesion molecule-1; VCAM-1: vascular cell adhesion molecule-1; ATP: adenosine triphosphate; eNOS: endothelial nitric oxide synthase; NF-κB: nuclear factor kappa-light-chain-enhancer of the activated B-cell; NO: nitric oxide; ↑: increase; ↓: decrease.