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Table 2 Putative mechanisms and factors involved in HHcy-related CVD in RA

From: Therapeutic potential of folic acid supplementation for cardiovascular disease prevention through homocysteine lowering and blockade in rheumatoid arthritis patients

Mechanism/factor contributing to HHcy-dependent CVD Comment
Oxidative stress [12, 44] Induction of endothelial dysfunction and atherosclerosis throughout impaired NO availability, increased lipid peroxidation and activation of NF-ƙB by Hcy-derived ROS, thus of inflammatory cascade
Chronic inflammation and immune activation [12, 14, 37, 38, 45] Inflammatory biomarkers (IL-1, IL-6, TNF-α, CRP) are related with impaired NO availability, endothelial dysfunction, arterial stiffness, and a prothrombotic status
Autoantibodies against peptides modified by homocysteine-thiolactone can worse inflammation and hence maintain an increased cardiovascular risk [14].
Pro-atherogenic lipid profile [4447] Healthy HDL molecules are tighly linked to PON1, an antioxidant enzyme which is diminished in RA
The remaining low HDL is pro-inflammatory and can no longer counteract LDL oxidation
Ox-LDL activates endothelium and favors atherosclerosis
High disease activity and severe radiological damage [6, 12, 14, 38, 44] They have been associated with HHcy and both reflect chronic inflammation.
The proatherogenic profile in RA highly depends on disease activity
Antiphospholipid autoantibodies and other thrombogenic molecules [21, 22, 38] The prevalence of aPL is high (28 %) in RA
In aPL-positive RA patients, aPL may interact with Hcy to increase the risk of thrombosis
Several procoagulant molecules are correlated with endothelial dysfunction and thrombosis
ADMA [14, 48] Increased plasma ADMA is independently associated with carotid atherosclerosis in RA
ADMA may cause endothelial dysfunction since higher serum levels have been associated with a decreased CFR in RA
Osteoprotegerina [49] OPG is increased in RA and is independently associated with carotid artery calcification in RA, probably to counteract increased RANKL production
Considering that HHcy has been associated with OPG in RA, and with respect to Hcy’s ability to stimulate RANKL, it is possible that OPG is a marker of Hcy-mediated CVD in RA.
Epigenetic and genetic factors [36, 50, 51] Interaction of HHcy with NFKB1-94ATTG ins/del polymorphism constitutively activated in RA patients to accentuate immune responses and that predispose RA patients to subclinical and accelerated atherosclerosis
RA is characterized by DNA hypomethylation which is implicated in atherosclerosis in the general population. It can be hypothesized that it may partly explain CVD in relation to HHcy in RA patients, but this is yet to be ascertained
  1. CVD cardiovascular diseases, NO nitric oxide, NF- ƙB Nuclear Factor ƙappa B, ROS reactive owxygen species, IL-1 interleukin 1, IL-6 interleukin 6, TNF-α tumor necrosis factor alpha, CRP C reactive protein, IFN-Ɣ, interferon gamma, HDL high density lipoprotein cholesterol, LDL low density lipoprotein cholesterol, PON1 paroxonase type 1, RA rheumatoid arthritis, ox-LDL oxidized low density lipoprotein cholesterol, IMT increased media-thickness, HHcy hyperhomocysteinemia, aPL antiphospholipid, ADMA asymmetric dymethylarginine, Hcy homocysteine, CFR coronary flow reserve, Osteoprotegerin a soluble glycoprotein which is an inibitor of the receptor activator of nuclear factor-ƙB (RANKL), OPG osteoprotegerin, CVD cardiovascularv diseases, DNA deoxyribonucleic acid