Statin Treatment Of Human Vascular Endothelial Cells Disrupts Caveolae And Increases Nitric Oxide Signaling

The statin family of drugs inhibits HMG‐CoA reductase, a rate‐limiting enzyme in the biosynthesis of cholesterol. Cholesterol is required for the formation of caveolae, a site of endothelial nitric oxide synthase (eNOS), the biosynthetic enzyme for nitric oxide (NO). This study tests the hypothesis that statins will disrupt the structure of caveolae and consequently alter eNOS function. Caveolae abundance was assessed using anti‐sera to caveolin‐1, a hallmark of caveolae, in immunocytochemistry and immunoblotting experiments. NO production was measured by two methods: an electrochemical sensor (Apollo 4000, World Precision Instruments) for short time points (<10min) and a modification of the Greiss reaction for longer time points (>30min). Lovastatin treatment (0.01–10μM, 24 h) of human umbilical vein endothelial cells produced a concentration‐dependent decrease in caveolin‐1 expression. Caveolin‐1 was enriched in buoyant sucrose‐gradient fractions of Triton‐X100‐solubilized lysates from control cells but undetectable in lovastatin treated cells. Conversely, lovastatin increased eNOS expression in whole cell lysates without significantly changing eNOS levels in buoyant sucrose‐gradient fractions. Bradykinin‐stimulated NO production was enhanced in lovastatin‐treated cells. These results indicate that treatment with lovastatin decreases caveolin‐1 and increases eNOS expression, implying that statin therapy may act directly on endothelial cells to disrupt caveolae and increase NO signaling. Such effects may contribute to the therapeutic actions of statin treatment in vivo Financial support provided by American Heart Association Scientist Development Grant #0530120N