Role of the eNOS Uncoupling and the Nitric Oxide Metabolic Pathway in the Pathogenesis of Autoimmune Rheumatic Diseases

Figure 2

Mechanisms of endothelial nitric oxide synthase (eNOS) uncoupling in endothelial dysfunction. A depletion of eNOS cofactor tetrahydrobiopterin (BH₄), an L-arginine deficiency, and an increase in endogenous eNOS inhibitor, asymmetric dimethylarginine (ADMA), leads to eNOS uncoupling. Produced by the uncoupled enzyme, superoxide scavenges nitric oxide (NO) leading to the peroxynitrite formation. Peroxynitrite (1) oxidizes BH₄, resulting in the eNOS uncoupling and perpetual superoxide production and subsequent peroxynitrite formation; (2) oxidizes low-density lipoproteins (LDL) forming oxidized LDL (ox-LDL) which in turn through the scavenger receptor, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), downregulate the enzyme expression. Furthermore, ox-LDL stimulate nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) and xanthine oxidase to produce reactive oxygen species (ROS) in excess and increase arginase activity leading to reduction in L-arginine availability for nitric oxide synthase (NOS) and subsequent eNOS uncoupling and impaired NO generation. Moreover, arginase via increased formation of polyamines and L-proline stimulates vascular smooth muscle cell proliferation and extracellular matrix deposition, thereby contributing to intimal hyperplasia and remodeling processes; (3) nitrosylates the cationic amino acid transporter, therefore inhibiting the L-arginine transport in endothelial cells and increasing the rate of arginine efflux; (4) increases the activity of protein-arginine methyl transferase (PRMTs) and inhibits that of dimethylarginine dimethylaminohydrolase (DDAH), resulting in elevated ADMA levels, which in turn via inhibition of NO synthesis and eNOS uncoupling enhance production of ROS. Oxidative stress in turn upregulates ADMA levels; (5) through activation of transcription factor, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) induces expression of inducible nitric oxide synthase (iNOS), arginase, and inflammatory and immune genes (cytokines, chemokines, adhesion molecules, acute phase proteins, regulators of apoptosis, and cell proliferation) potentiating inflammation via further recruitment of adaptive and innate immune cells and ROS generation, leading to persistence of inflammation and disease progression. Abbreviations: eNOS: endothelial nitric oxide synthase; NO: nitric oxide; BH₄: tetrahydrobiopterin; ADMA: asymmetric dimethylarginine; O₂^-: superoxide; ONOO-: peroxynitrite; BH₂: dihydrobiopterin; DHFR: dihydrofolate reductase; ox-LDL: oxidized LDL; NADPH oxidase: nicotinamide adenine dinucleotide phosphate oxidase; LDL: low-density lipoproteins; iNOS: inducible nitric oxide synthase; NF-κB: nuclear factor kappa light-chain-enhancer of activated B cells; DDAH: dimethylarginine dimethylaminohydrolase; PRMT: protein arginine methyl transferase.