CMO2 and Human Monocyte Differentiation: Potential mechanisms of lycopene in the prevention of atherosclerosis

Abstract

Monocyte‐derived macrophages are precursors of the lipid‐laden foam cells in atherosclerotic fatty‐streak lesions. Depending on diet, circulating monocytes are exposed to lipoprotein packaged carotenoids. Low plasma carotenoid levels have been associated with increased risk of cardiovascular disease. We report that lycopene may alter monocyte‐macrophage phenotype and function through regulating β‐carotene 9',10′‐monooxygenase (CMO2) expression. We demonstrated that the CMO2 gene is differentially expressed in undifferentiated monocytes and monocyte‐derived macrophages. CMO2 is expressed in human primary monocytes and monocytic THP‐1 cells. Reducing CMO2 expression accompanied phorbol 12‐myristate 13‐acetate (PMA) induced differentiation of THP‐1 cells to the macrophage phenotype. Lycopene treatment of THP‐1 cells significantly increased CMO2 mRNA and protein levels. Induced overexpression of CMO2 in THP‐1 cells suppressed NFκB activity but increased PPAR reporter activity, suggesting that elevated CMO2 induces PPAR function. These studies provide the first evidence for the biological role of CMO2 in regulating monocyte differentiation via modulation of inflammation related signaling pathways. Targeting CMO2 with carotenoids may thus serve as a nutritional and therapeutic approach to attenuate vascular wall inflammation and slow the progression of atherosclerosis. (NIH HD42174, Muma Family Endowment)