Rheumatoid arthritis (RA) is a systemic autoimmune disease associated with a markedly increased risk of cardiovascular disease (CVD) that is not fully explained by traditional risk factors. Lipoprotei Show more
Rheumatoid arthritis (RA) is a systemic autoimmune disease associated with a markedly increased risk of cardiovascular disease (CVD) that is not fully explained by traditional risk factors. Lipoprotein(a) [Lp(a)], a genetically determined lipoprotein with proatherogenic, prothrombotic, and proinflammatory properties, has emerged as a potential contributor to this excess cardiovascular burden. Growing evidence suggests that Lp(a) may represent a mechanistic link between chronic inflammation, immune dysregulation, and accelerated atherosclerosis in RA. This narrative review synthesizes evidence from observational studies, mechanistic research, genetic analyses, biomarker investigations, and emerging therapeutic trials examining Lp(a) in RA. Relevant literature was identified through comprehensive searches of major biomedical databases, with emphasis on studies addressing pathophysiology, cardiovascular outcomes, disease activity, and treatment effects on Lp(a). RA patients frequently exhibit elevated Lp(a) levels, particularly in the presence of active systemic inflammation. Lp(a) contributes to vascular injury through enhanced arterial wall retention, carriage of oxidized phospholipids, endothelial activation, and impaired fibrinolysis. Clinical studies associate elevated Lp(a) with subclinical atherosclerosis, arterial stiffness, and increased cardiovascular events in RA, independent of conventional lipid parameters. Inflammatory cytokines, particularly interleukin-6 (IL-6), appear to modulate Lp(a) metabolism, providing a biological rationale for the Lp(a)-lowering effects observed with IL-6 receptor blockade. Advances in standardized assays, genetic insights into LPA polymorphisms, and novel RNA-based therapies have revitalized interest in Lp(a) as both a biomarker and therapeutic target in RA. Lp(a) occupies a critical intersection between inflammation and atherosclerosis in RA. Incorporating Lp(a) into cardiovascular risk stratification and exploring targeted therapies may enable more precise, integrated management of cardiovascular risk in RA patients, warranting dedicated prospective studies. Show less
Erk-5, a member of the MAPK superfamily, has a catalytic domain similar to Erk1/2 and a unique C-terminal domain enabling binding with transcription factors. Aberrant vascularization in the Erk5-null Show more
Erk-5, a member of the MAPK superfamily, has a catalytic domain similar to Erk1/2 and a unique C-terminal domain enabling binding with transcription factors. Aberrant vascularization in the Erk5-null mice suggested a link to angiogenesis. Ectopic expression of constitutively active Erk5 blocks endothelial cell morphogenesis and causes HIF1-alpha destabilization/degradation. However the mechanisms by which endogenous Erk5 regulates angiogenesis remain unknown. We show that Erk5 and its activating kinase MEK5 are the upstream mediators of the anti-angiogenic signal by the natural angiogenesis inhibitor, pigment epithelial-derived factor (PEDF). We demonstrate that Erk5 phosphorylation allows activation of PPARgamma transcription factor by displacement of SMRT co-repressor. PPARgamma, in turn is critical for NFkappaB activation, PEDF-dependent apoptosis, and anti-angiogenesis. The dominant negative MEK5 mutant and Erk5 shRNA diminished PEDF-dependent apoptosis, inhibition of the endothelial cell chemotaxis, and angiogenesis. This is the first evidence of Erk5-dependent transduction of signals by endogenous angiogenesis inhibitors. Show less