The Effect of Prednisone on Atherogenesis as Studied in the Macrophage Foam Cell Formation Model System.

Atherosclerosis, Dyslipidemias, Diabetes

Glucocorticoids (GCs) are a class of endogenous steroid hormones produced by the adrenal glands and controlled by the hypothalamic-pituitary-adrenal axis (HPA). One of the mechanisms of their action is achieved through ligand-receptor attachment to a class of cytosolic steroid hormone receptors termed Glucocorticoid Receptors (GRs). The formed ligand-receptor complex is a transcription factor involved in gene activation of anti-inflammatory products or repression of pro-inflammatory products \[1\]. Synthetic forms of GCs are a group of anti-inflammatory and immunosuppressive medications (e.g. Prednisone) that are widely used in clinical practice to treat inflammatory diseases (e.g. Rheumatoid Arthritis, Vasculitis, Asthma). The effectiveness of this class of drugs is limited by numerous adverse effects that include, but not limited to, insulin resistance, glucose intolerance, dyslipidemia, and hypertension, all of which are well known risk factors for cardiovascular diseases (CVD) \[2,3\]. Furthermore, recent research suggest that inflammation has a key role in development of CVD and can predict prognosis \[4\]. Inflammatory cells have an important role in the development of atherosclerotic lesion in the arteries. Blood monocyte-derived macrophages are involved in this process, and they infiltrate the lesion where they take up various forms of lipids (cholesterol - rich LDL, and oxidized LDL) as well as triglycerides - rich VLDL), followed by the formation of lipid-laden foam cells, the hallmark of early atherogenesis. Inflammatory cells and molecules as well as proteolytic enzymes secreted from inflammatory cells in the atherosclerotic lesion, have a central role in destabilizing the plaque (vulnerable plaque) leading to its rupture, which, in turn, induces thrombosis, and initiating acute coronary events \[4,5\]. Based on our understanding of the involvement of inflammation in the early development of atherosclerotic lesion, and our experience with the anti-inflammatory effects of synthetic GCs, a hypothesis emerged suggesting this class of drugs as a way to inhibit early atherosclerotic plaque formation, and to attenuate CVDs \[6\]. Research results in this field are surprising because while glucocorticoids treatment in humans increase the risk of CVDs \[6,7,8,9\], animal models shows the opposite, atheroprotection was shown in rabbits \[10,11,12\] and mice \[13,14,15\]. This paradox may be explained partially by the fact that clinical studies in this field are mainly conducted in patients with predisposing factors to develop CVD, either because of pre-existing traditional risk factors like Diabetes and Hyperlipidemia, or because of the pre-existing medical condition they are being treated for with GCs (e.g. Rheumatoid Arthritis). Mechanism based research to study the effects of GCs on atherogenesis, without confounding factors, is lacking. Only few studies were performed on GCs in healthy subjects but none of them explored their effects on foam cell formation \[16,17\]. Our study thus aims to further our understanding of the role of specific glucocorticoid, prednisone, in the process of atherogenesis. In order to achieve that we plan to study the following: 1. The effects of five days of treatment with prednisone on serum lipid concentration and oxidative stress. 2. an Ex-vivo study is planned where the serum of healthy human subjects treated with Prednisone, will be introduced to J774A.1 murine macrophage-like cell line, a well-studied macrophage foam cell formation model.

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