Fenretinide treatment accelerates atherosclerosis development in apoE‐deficient mice in spite of beneficial metabolic effects

Abstract

Background and Purpose: 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.Experimental Approach: To this aim, nine-week-old apoE-knockout (EKO) female mice were fed for twelve weeks a Western diet, without (control) or with (0.1% w/ w) fenretinide. As a reference, wild-type (WT) mice 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.Key Results: Fenretinide treatment significantly lowered body weight, glucose levels and plasma levels of total cholesterol, triglycerides, and phospholipids. In the liver, fenretinide remarkably reduced hepatic 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. Treatment resulted in a threefold increase of total leukocytes (WT and EKO) and raised the activated/resting monocyte ratio in EKO mice. Finally, atherosclerosis development was markedly increased at the aortic arch, thoracic and abdominal aorta of fenretinide-treated mice. Conclusions and Implications:We provide the first evidence that, despite beneficial metabolic effects, fenretinide treatment may enhance the development of atherosclerosis.

Acacetin exerts antioxidant potential against atherosclerosis through Nrf2 pathway in apoE−/− Mice

“…They finally conclude that bufalin may modulate immune responses not only through increasing monocyte (CD11b) population and T‐ and B‐cell proliferation, but also by increasing macrophage phagocytosis in leukaemic mice in vivo 42 . Marco Busnelli and colleagues found that fenretinide, a synthetic retinoid derivative, could induce spleen abnormally enlarged and markedly increased atherosclerotic lesions at the aortic arch, thoracic and abdominal aorta of fenretinide‐treated mice, just the similar results in our control (western diet) group 43 . In our present study, we found that mice treated with acacetin had lower spleen/body weight ratio and it may be because acacetin regulates spleen immunity function, decreasing monocytes or promoting monocyte‐macrophage to M2 differentiation.…”

“…We speculate that, mice, just the similar results in our control (western diet) group. 43 In our present study, we found that mice treated with acacetin had lower spleen/body weight ratio and it may be because acacetin regulates spleen immunity function, decreasing monocytes or promoting monocyte-macrophage to M2 differentiation.…”

Aortic Gene Expression Profiles Show How ApoA-I Levels Modulate Inflammation, Lysosomal Activity, and Sphingolipid Metabolism in Murine Atherosclerosis

“…Additionally, it should be noted that apoE has been recognized to possess anti-inflammatory and immunosuppressive effects and, as a consequence, apoE deficiency in mice is associated with an increased T-cell activation and inflammatory response, 68 accompanied by spleen and lymph node enlargement. 29 , 69 …”

“…Aortas were then snap-frozen in liquid nitrogen for RNA-seq analyses (n=3) or longitudinally opened, pinned flat on a black wax surface in ice-cold PBS, and photographed unstained for en face analysis (n=3–9). 26 – 29 For the histological evaluation of the aortic sinus, hearts were harvested, processed, and stained with haematoxylin and eosin as previously described (n=3–6). 26 – 29 Both aortic en face and aortic sinus histology were performed in accordance with American Heart Association recommendations.…”

“… 26 – 29 For the histological evaluation of the aortic sinus, hearts were harvested, processed, and stained with haematoxylin and eosin as previously described (n=3–6). 26 – 29 Both aortic en face and aortic sinus histology were performed in accordance with American Heart Association recommendations. 30 …”