Mechanism/factor contributing to HHcy-dependent CVD | Comment |
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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]. | |
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 | |
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. | |
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 |