High levels of cholesterol are a major risk factor for atherosclerosis and, consequently, heart attacks and strokes. But how does cholesterol affect atherogenesis? Partly, report Jung San Huang and co-workers, by suppressing the responsiveness of vascular cells to the anti-atherosclerotic molecule transforming growth factor β (TGF-β; see ). TGF-β antagonizes many key atherogenic events (for example, inflammation of blood vessel walls); so modulating responsiveness to TGF-β is likely to affect the development of atherosclerosis. The authors show that cholesterol treatment suppresses TGF-β-induced signalling in several cell types, including endothelial cells. It does this, they report, by increasing the accumulation of TGF-β receptors in lipid microdomains and facilitating the degradation of TGF-β. By contrast, agents that lower or deplete cholesterol promote TGF-β-induced signalling. Finally, the authors show that TGF-β responsiveness is suppressed in the aortic endothelium of atherosclerosis-prone mice fed a cholesterol-rich diet. These new insights into how cholesterol contributes to atherogenesis could lead to the development of new strategies for the treatment and prevention of atherosclerosis.
