Albion College Faculty Publications

Isozaki, T., Rabquer, B. J., Ruth, J. H., Haines, G. K., & Koch, A. E. (2013). ADAM-10 is overexpressed in rheumatoid arthritis synovial tissue and mediates angiogenesis. Arthritis and Rheumatism, 65(1), 98-108.

Abstract:

Objective – To examine the expression of ADAM-10 in rheumatoid arthritis (RA) synovial tissue (ST) and the role it plays in angiogenesis. Methods ADAM-10 expression was determined using immunohistology, Western blotting, and quantitative polymerase chain reaction. In order to examine the role of ADAM-10 in angiogenesis, we performed in vitro Matrigel tube formation and chemotaxis assays using human microvascular endothelial cells (HMVECs) transfected with control or ADAM-10 small interfering RNA (siRNA). To determine whether ADAM-10 plays a role in angiogenesis in the context of RA, we performed Matrigel assays using a coculture system of HMVECs and RA synovial fibroblasts.

Results – Endothelial cells and lining cells within RA ST expressed high levels of ADAM-10 compared with cells within osteoarthritis ST and normal ST. ADAM-10 expression was significantly elevated at the protein and messenger RNA levels in HMVECs and RA synovial fibroblasts stimulated with proinflammatory mediators compared with unstimulated cells. ADAM-10 siRNAtreated HMVECs had decreased endothelial cell tube formation and migration compared with control siRNAtreated HMVECs. In addition, ADAM-10 siRNAtreated HMVECs from the RA synovial fibroblast coculture system had decreased endothelial cell tube formation compared with control siRNAtreated HMVECs.

Conclusion – These data show that ADAM-10 is overexpressed in RA and suggest that ADAM-10 may play a role in RA angiogenesis. ADAM-10 may be a potential therapeutic target in inflammatory angiogenic diseases such as RA.

Rabquer, B. J., & Koch, A. E. (2012). Recent developments in adhesion in rheumatoid arthritis. International Journal of Clinical Rheumatology, 7(3), 287-296.

Abstract: Rheumatoid arthritis is a chronic autoimmune disease characterized by inflammation, angiogenesis and eventual joint destruction. Adhesion molecules play primary roles in each of these facets of the disease, regulating leukocyte recruitment and retention, angiogenesis and synovial tissue organization. Current studies investigating adhesion molecules in rheumatoid arthritis are aimed at exploring the role of novel adhesion molecules in the pathogenesis of the disease, and investigating the potential use of established adhesion molecules as therapeutic targets or biomarkers of disease activity. In this review we will discuss recent investigations in each of these areas.

Rabquer, B. J., & Koch, A. E. (2012). Angiogenesis and Vasculopathy in Systemic Sclerosis: Evolving Concepts. Current Rheumatology Reports, 14(1), 56+.

Abstract: Systemic sclerosis (scleroderma [SSc]) is a multifactorial disease characterized by inflammation, extensive and progressive fibrosis, and multiple vasculopathies. The
vascular manifestations can be seen early in the pathogenesis of the disease and include malformed capillaries, Raynaud’s phenomenon, and digital ulcers. As the disease progresses, the vasculopathy proceeds to significant clinical manifestations, including renal crisis and pulmonary arterial hypertension. Moreover, later stages of the disease are marked by increasingly avascular areas. Despite the obliteration of microvascular structures, compensatory vasculogenesis and angiogenesis do not occur normally. This is in spite of a general increase in many potent angiogenic factors. Recent studies are beginning to examine this paradox and subsequent paucity of an angiogenic response in SSc. In this review, we discuss these findings and examine the role that chemokine and growth factor receptors, proteases, adhesion molecules, and transcription factors play in the dysregulation of angiogenesis in SSc.

Thacker, S. G., Zhao, W., Smith, C. K., Luo, W., Wang, H., Vivekanandan-Giri, A., Rabquer, B. J., et al. (2012). Type I interferons modulate vascular function, repair, thrombosis, and plaque progression in murine models of lupus and atherosclerosis. Arthritis & Rheumatism, 64(9), 2975-2985.

Abstract: Objective Patients with systemic lupus erythematosus (SLE) have a notable increase in atherothrombotic cardiovascular disease (CVD) which is not explained by the Framingham risk equation. In vitro studies indicate that type I interferons (IFNs) may play prominent roles in increased CV risk in SLE. However, the in vivo relevance of these findings, with regard to the development of CVD, has not been characterized. This study was undertaken to examine the role of type I IFNs in endothelial dysfunction, aberrant vascular repair, and atherothrombosis in murine models of lupus and atherosclerosis. Methods Lupus-prone New Zealand mixed 2328 (NZM) mice and atherosclerosis-prone apolipoprotein E– knockout (apoE−/−) mice were compared to mice lacking type I IFN receptor (INZM and apoE−/−IFNAR−/− mice, respectively) with regard to endothelial vasodilatory function, endothelial progenitor cell (EPC) function, in vivo neoangiogenesis, plaque development, and occlusive thrombosis. Similar experiments were performed using NZM and apoE−/− mice exposed to an IFNα-containing or empty adenovirus. Results Loss of type I IFN receptor signaling improved endothelium-dependent vasorelaxation, lipoprotein parameters, EPC numbers and function, and neoangiogenesis in lupus-prone mice, independent of disease activity or sex. Further, acute exposure to IFNα impaired endothelial vasorelaxation and EPC function in lupus-prone and non–lupus-prone mice. Decreased atherosclerosis severity and arterial inflammatory infiltrates and increased neoangiogenesis were observed in apoE−/−IFNAR−/− mice, compared to apoE−/− mice, while NZM and apoE−/− mice exposed to IFNα developed accelerated thrombosis and platelet activation. Conclusion These results support the hypothesis that type I IFNs play key roles in the development of premature CVD in SLE and, potentially, in the general population, through pleiotropic deleterious effects on the vasculature.