Loading-induced ERK activation was dependent upon the presence and concentration of pericellular FGF-2, suggesting a functional role for this matrix-bound growth factor in chondrocyte mechanotransduction.

The increased burden of cardiovascular disease in patients with rheumatoid arthritis and systemic lupus erythematosus has recently become the focus of intense investigation. Pro-atherogenic risk factors and dysregulated inflammation are the main culprits, leading to enhanced atherosclerosis in subgroups of patients with inflammatory diseases. Common molecular pathways shared by atherosclerosis and inflammatory disease may be involved. In this review we map the key determinants of the increased incidence of cardiovascular disease in patients with inflammatory diseases at each step of the atherogenesis. IntroductionResearch during the past 20 years has driven a major shift in how atherosclerosis is conceptualized. Initially branded as a passive accumulation of lipids in the vessel wall, atherosclerosis is now recognised as an 'inflammatory disease' [1]. Striking similarities can be identified between atherosclerosis and prototypical inflammatory diseases (Figure 1). In parallel, there is growing evidence that cardiovascular disease (CVD) is the leading cause of mortality in patients with chronic inflammatory diseases [2], including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's disease and systemic sclerosis. This review first summarizes the impact of CVD on the lives of patients with inflammatory diseases. Second, we map the key molecular determinants of the increased prevalence of CVD in patients with inflammatory diseases at each step of the progression of atherosclerosis (initiation, progression and thrombotic complications). We focus on RA and SLE, for which more evidence is currently available. The clinical impact of atherosclerosis in inflammatory diseasesAtherosclerosis and rheumatoid arthritis Cardiovascular manifestations such as pericarditis, myocarditis and atrioventricular block are classic complications of RA and SLE. However, most of the cardiovascular mortality in RA patients is not due to these manifestations but rather to ischaemic heart disease secondary to coronary atherosclerosis [3]. In the Nurses' Health Study [4], patients with RA had more than twofold greater risk for myocardial infarction (MI) compared with patients without RA. Worryingly, RA patients are almost six times more likely to have had an undiagnosed MI and twice as likely to experience sudden death [5]. RA patients are also far less likely to report forewarning symptoms, such as angina [5,6], potentially hampering early detection of atherosclerotic disease.In support of these observations, RA patients have an increased prevalence of subclinical atherosclerosis, with a greater incidence of carotid artery plaque and increased carotid intima/media thickness (IMT) [7,8] as well as multivessel coronary artery disease compared with control individuals [9]. Systemic lupus erythematosus and cardiovascular diseaseThree decades ago, Urowitz and coworkers [10] recognized that CVD and MI were major causes of mortality in patients with SLE. In fact, patients with SLE are five or six times more likely to hav...

Smooth muscle cells (SMC) contribute to the development and stability of atherosclerotic lesions. The molecular mechanisms that mediate their properties are incompletely defined. We employed proteomics and in vitro functional assays to identify the unique characteristics of intimal SMC isolated from human carotid endarterectomy specimens and medial SMC from thoracic aortas and carotids. We verified our findings in the Tampere Vascular Study. Human atheroma-derived SMC exhibit decreased expression of mitochondrial proteins ATP Synthase subunit-beta and Aldehyde dehydrogenase 2, and decreased mitochondrial activity when compared to control SMC. Moreover, a comparison between plaque-derived SMC isolated from patients with or without recent acute cerebrovascular symptoms uncovered an increase in Annexin A1, an endogenous anti-inflammatory protein, in the asymptomatic group. The deletion of Annexin A1 or the blockade of its signaling in SMC resulted in increased cytokine production at baseline and after stimulation with the pro-inflammatory cytokine Tumor Necrosis Factor α. In summary, our proteomics and biochemical analysis revealed mitochondrial damage in human plaque-derived SMC as well as a role of Annexin A1 in reducing the production of pro-inflammatory mediators in SMC.

Rheumatoid arthritis (RA) is an autoimmune disease affecting approximately 1% of the population. Patients have reduced life expectancy and the leading cause of death is cardiovascular disease (CVD), with patients experiencing at least a 2‐fold increased risk of myocardial infarction. RA is recognized as an independent risk factor for CVD. Inflammation is a key contributor to the pathogenesis of atherosclerosis and cardiovascular events. As a common catalyst of both diseases, inflammation is the likely cause of increased prevalence of CVD in the RA population. Abating disease‐related inflammation in RA may be an effective strategy in reducing CVD risk. Several other therapies used to modify cardiovascular risk factors in the general population such as statins and angiotensin‐converting enzyme inhibitors are under investigation in patients with RA. This review discusses the parallels in the pathology of RA and atherosclerosis and discusses current therapies for RA and how they affect cardiovascular risk.

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