Abstract
Chronic inflammation causes dysregulated expression of microRNAs. Aberrant microRNA expression is associated with endothelial dysfunction. In this study we determined whether TNF-α inhibition impacted the expression of miRNA-146a-5p and miRNA-155-5p, and whether changes in the expression of these miRNAs were related to inflammation-induced changes in endothelial function in collagen-induced arthritis (CIA). Sixty-four Sprague-Dawley rats were divided into control (n = 24), CIA (n = 24) and CIA+etanercept (n = 16) groups. CIA and CIA+etanercept groups were immunized with bovine type-II collagen, emulsified in incomplete Freund’s adjuvant. Upon signs of arthritis, the CIA+etanercept group received 10mg/kg of etanercept intraperitoneally, every three days. After six weeks of treatment, mesenteric artery vascular reactivity was assessed using wire-myography. Serum concentrations of TNF-α, C-reactive protein, interleukin-6, vascular adhesion molecule-1 (VCAM-1) and pentraxin-3 (PTX-3) were measured by ELISA. Relative expression of circulating miRNA-146a-5p and miRNA-155-5p were determined using RT-qPCR. Compared to controls, circulating miRNA-155-5p, VCAM-1 and PTX-3 concentrations were increased, and vessel relaxation was impaired in the CIA (all p<0.05), but not in the CIA+etanercept (all p<0.05) groups. The CIA group had greater miRNA-146a-5p expression compared to the CIA+etanercept group (p = 0.005). Independent of blood pressure, miRNA-146a-5p expression was associated with increased PTX-3 concentrations (p = 0.03), while miRNA-155-5p expression was associated with impaired vessel relaxation (p = 0.01). In conclusion, blocking circulating TNF-α impacted systemic inflammation-induced increased expression of miRNA-146a-5p and miRNA-155-5p, which were associated with endothelial inflammation and impaired endothelial dependent vasorelaxation, respectively.
Highlights
Rheumatoid arthritis (RA) is associated with a greater risk of cardiovascular events and mortality [1]
For the animals included in this study the onset of arthritis, as indicated by joint swelling and oedema, occurred in the collagen-induced arthritis (CIA) and CIA+etanercept groups within 21–28 days after the primary immunization [30]
The serum concentrations of TNF-α, interleukin 6 (IL-6) and C-reactive protein (CRP) were increased in the CIA and CIA+etanercept groups compared to the control group
Summary
Rheumatoid arthritis (RA) is associated with a greater risk of cardiovascular events and mortality [1]. Subclinical vascular changes including endothelial dysfunction, arteriosclerosis and atherosclerosis are more prevalent in RA compared to the general population and contribute to the increased cardiovascular disease (CVD) prevalence in RA [2]. Systemic inflammation is associated with impaired vascular function, independent of traditional risk factors in RA [3]. The mechanisms whereby systemic inflammation impairs vascular function are currently under investigation [4]. Inflammation-induced endothelial activation and dysfunction are considered important early predictors of atherosclerotic CVD, arterial stiffness and heart failure [6,7,8]. VCAM-1 enables leukocyte binding and migration to the arterial wall intima, making it a sensitive marker of endothelial activation and early atherosclerosis [10, 11]. Local production of PTX-3 impairs endothelial function and amplifies vascular inflammation [14]. Endothelial inflammation reduces nitric oxide (NO) bioavailability which results in impaired endothelial-dependent vasodilation and endothelial dysfunction [15]
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