Endothelial injury in rheumatoid arthritis: a crosstalk between dimethylarginines and systemic inflammation

Abstract

BackgroundSymmetric (SDMA) and asymmetric (ADMA) dimethylarginines have emerged as novel biomarkers of cardiovascular disease (CVD) in several disease settings associated with atherosclerosis. Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by high CVD mortality and morbidity. ADMA and SDMA levels are abnormal in RA patients, but their correlation with assessments of endothelial function and structure remains unknown. We aimed to investigate whether SDMA and ADMA are associated with carotid intima media thickness (cIMT) and arterial stiffness as well as non-invasive assessments of in vivo micro- and macrovascular endothelial function in RA patients with high systemic inflammatory load.MethodADMA and SDMA levels were measured using immunoassays in 197 RA individuals. Twenty-six of these [23 (86.4%) females, median age 70, quartiles (60, 73)] were identified as having high inflammatory markers [erythrocyte sedimentation rate (ESR) >25 mm/hr and C-reactive protein (CRP) > 5 mg/L], and were compared to the remainder of the cohort. Patients underwent assessments of microvascular endothelium-dependent and endothelium-independent function [laser Doppler imaging with iontophoresis of acetylcholine (Ach) and sodium-nitroprusside (SNP) respectively], macrovascular endothelium-dependent and endothelium-independent function (flow-mediated dilatation and glyceryl-trinitrate-mediated dilation respectively), and vascular morphology [pulse wave analysis, and carotid intima media thickness (cIMT)].ResultsSignificant interactions with inflammation were detected in the associations between ACh and both SDMA (p = 0.014) and ADMA:SDMA ratio (p = 0.027), as well as between SNP and SDMA (p = 0.042) and between arterial stiffness and ADMA:SDMA (p = 0.036), with the associations being stronger in the patients with high inflammatory markers in each case.ConclusionsBesides their emerging role as markers of endothelial dysfunction SDMA and ADMA may promote endothelial injury in RA as mediators of the adverse effects of systemic inflammation on micro- and macrovasculature respectively in patients with active disease.

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

“…In patients with high disease activity and no overt atherosclerotic disease or classic risk factors, high plasma ADMA levels significantly correlated with IMT [67], coronary flow reserve (CFR) [56], and pulse wave velocity (PWV) [58], whereas in those with evident atherosclerosis and CV risk factors, negative correlation between ADMA and FMD [65] and carotid IMT (cIMT) [62,68] was found. In the latter subgroup of patients also, a positive relation was observed between the ADMA : SDMA ratio (suggested as the index of dimethylarginine dimethylaminohydrolase activity) and microvascular endothelial function [68] and arterial stiffness [62]. However, these relationships were not observed in RA patients with low and moderate disease activities-although structural and functional changes in vessels and heart were detected by means of multiple noninvasive, validated methods including cIMT, FMD, CFR, PWV, laser Doppler, and subendocardial viability ratio (SEVR), no associations between dimethylarginines and assessments of vascular morphology and function were found [56,61,65].…”

“…Negative regulation of NO synthesis can also be mediated through overproduction of methylated arginine analogues such as ADMA. Recently, many clinical studies have demonstrated that plasma levels of ADMA were elevated in RA patients regardless of the presence of cardiovascular disease [55][56][57][58][59][60][61][62][63][64][65][66][67]. Furthermore, ADMA has been reported to be related to indices of endothelial dysfunction or subclinical atherosclerosis in some [56,65,68], but not all, conducted studies [58,60,61,67,68].…”

“…Furthermore, ADMA has been reported to be related to indices of endothelial dysfunction or subclinical atherosclerosis in some [56,65,68], but not all, conducted studies [58,60,61,67,68]. In patients with high disease activity and no overt atherosclerotic disease or classic risk factors, high plasma ADMA levels significantly correlated with IMT [67], coronary flow reserve (CFR) [56], and pulse wave velocity (PWV) [58], whereas in those with evident atherosclerosis and CV risk factors, negative correlation between ADMA and FMD [65] and carotid IMT (cIMT) [62,68] was found. In the latter subgroup of patients also, a positive relation was observed between the ADMA : SDMA ratio (suggested as the index of dimethylarginine dimethylaminohydrolase activity) and microvascular endothelial function [68] and arterial stiffness [62].…”

Methotrexate and Vasculoprotection: Mechanistic Insights and Potential Therapeutic Applications in Old Age

“…This might account for the reduced coronary flow reserve, and consequent increased risk of ischaemic heart disease, reported in patients with rheumatoid arthritis and other similar autoimmune conditions [68]. In addition to the potential role of inflammatory pathways and traditional cardiovascular risk factors, the accumulation of the potent endogenous inhibitor of eNOS synthase, asymmetric dimethylarginine (ADMA), might also play a role in the pathogenesis of endothelial dysfunction in rheumatoid arthritis [69][70][71].…”

Endothelial function and its role in the formation of cardiovascular pathology in patients with rheumatoid arthritis

“…(2017) у больных РА с умеренной и высокой активностью при высоком содержании С-реактивного белка и в значительной степени увеличенной скорости оседания эритроцитов были констатированы более низкие значения поток-зависимой вазодилатации эндотелия и более высокие концентрации циркулирующих маркёров ЭД. Это свидетельствовало об ухудшении функций эндотелия при нарастании активности воспаления у больных РА [25].…”