Lenalidomide Attenuates High Fat Diet Induced‐Cyclooxygenase‐2 Levels in Human Vascular Smooth Muscle Cells
Authors: Bartel Robyn , Rahman Sanna , Decourt Boris , Sweazea Karen L. , Gonzales Rayna J. 
Published: June 2021

Poor diet and nutrition, e.g. consumption of excess saturated fatty acids, play a large role in the development of obesity, a significant risk factor for cardiovascular disease. Experimental and clinical studies suggest that obesity is a low‐grade systemic inflammatory disease. Along with inflammation, obesity can also trigger systemic oxidative stress, and together can initiate pathological mechanisms that lead to obesity‐associated organ damage such as endothelial dysfunction and vascular smooth muscle inflammation. Lenalidomide is a derivative of thalidomide and is currently used as a drug to treat multiple myeloma cancer. Lenalidomide exhibits potent cytokine modulatory capacity by inhibition of TNFalpha expression during conditions of cellular stress and in an experimental rodent model of obesity. The impact of lenalidomide on modulating inflammation and oxidative stress in the human vasculature has not been investigated. Therefore, the present study investigated the effects of lenalidomide on cyclooxygenase‐2 (COX‐2) levels (inflammation) and ROS (oxidative stress) in primary human vascular smooth muscle cells treated with high fat exposure. Our previous studies have demonstrated that exposure to palmitic acid, a saturated and high‐density fat, results in oxidative stress and an inflammatory response. Others have demonstrated that increased oxidative stress and inflammation occurs as a result of enhanced production of ROS. In this study, primary male aortic vascular smooth muscle cells at passage 7 were treated with vehicle or palmitate (100 μM) for 18 h with lenalidomide (0.5, 1.0, or 5 μM) or vehicle added at the 15 hour time point to investigate a reversal effect. Following treatment, cells were isolated, homogenized, and analyzed for COX‐2 levels using western analysis. Consistent with previous data, palmitate dose dependently increased basal COX‐2 protein levels; the highest dose of palmitate concomitantly increased production of prostaglandin E2. Lenalidomide reversed palmitate‐induced COX‐2, but only at the highest dose. Palmitate do not alter TNFalpha levels; however, lenalidomide elicited an increase in TNFalpha levels independent of palmitate. Superoxide production was analyzed using a 96‐well total cellular superoxide detection assay kit (Abcam). Lenalidomide, but not palmitate, increased oxidative stress and this response was dose dependent. In conclusion, high fat exposure elicits an inflammatory response in cultured primary human vascular smooth muscle, but this response appears to be independent of local cytokine or ROS production. Lenalidomide, although effective at reversing palmitate‐induced COX‐2, alone augments the pro‐inflammatory mediators, COX‐2 and TNFalpha, as well as promotes oxidative stress independent of high fat exposure in human vascular smooth muscle cells.

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Valley Research Partnership P2 VRP27Award (RJG)

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.