Fenretinide treatment in apoE-KO mice severely alters erythrocyte turnover and causes a dramatic increase of circulating leukocytes resulting in a worsened atherosclerosis development

Aim. Fenretinide, a synthetic retinoid derivative first investigated for cancer prevention and treatment, has been shown to ameliorate glucose tolerance, improve plasma lipid profile and reduce body fat mass. These effects, together with its ability to inhibit ceramide synthesis, suggest that fenretinide may have an anti‐atherosclerotic action. Methods. Nine‐week‐old apoE‐knockout (EKO) female mice were fed for twelve weeks a Western diet, without or with (0.1% w/w) fenretinide. Wild‐type mice, taken as a reference, were treated similarly. Growth and metabolic parameters were monitored throughout the study. Atherosclerosis development was evaluated in the aorta and at the aortic sinus. Blood and lymphoid organs were further characterized with thorough cytological/histological and immunocytofluorimetric analyses. Results. Fenretinide treatment significantly lowered body weight, glucose levels and plasma levels of total cholesterol, triglycerides, and phospholipids. In the liver, fenretinide remarkably reduced glycogenosis and steatosis driven by the Western diet. Treated spleens were abnormally enlarged, with severe follicular atrophy and massive extramedullary haematopoiesis. Severe renal hemosiderin deposition was observed in treated EKO mice. Fenretinide administration increased platelet activation and the number of circulating total leukocytes with a raised activated/resting monocyte ratio in EKO mice. Finally, atherosclerosis development was severely worsened in fenretinide‐treated mice. Plaques of treated mice were characterized by an increased collagen content and a larger necrotic core, whereas the area occupied by macrophages, foam cells and neutral lipids was comparable between treated and untreated mice. Conclusions. We provide the first evidence that, despite beneficial metabolic effects, fenretinide treatment may enhance the development of atherosclerosis.