Saturday, March 26, 2011

7. Statins, Caveolin, and Muscular Dystrophy

Lipid rafts are crucial centers for transport of substances (both nutrients and ions) across cell membranes and as a cell signaling domain in essentially all mammalian cells. Caveolae ("little caves") are microdomains within lipid rafts, which are enriched in a substance called caveolin (Gratton et al., 2004). Caveolin has received increasing attention of late due to the widespread role it plays in cell signaling mechanisms and the transport of materials between the cell and the environment (Smart et al., 1999).

Statins are known to interfere with caveolin production, both in endothelial cells (Feron et al., 2001) and in heart muscle cells, where they've been shown to reduce the density of caveolae by 30% (Calaghan, 2010). People who have a defective form of caveolin-3, the version of caveolin that is present in heart and skeletal muscle cells, develop muscular dystrophy as a consequence (Minetti et al., 1998). Mice engineered to have defective caveolin-3 that stayed in the cytoplasm instead of binding to the cell wall at lipid rafts exhibited stunted growth and paralysis of their legs (Sunada et al., 2001). Caveolin is crucial to cardiac ion channel function, which, in turn, is essential in regulating the heart beat and protecting the heart from arrhythmias and cardiac arrest (Maguy et al, 2006). In arterial smooth muscle cells, caveolin is essential to the generation of calcium sparks and waves, which, in turn, are essential for arterial contraction and expansion, to pump blood through the body (Taggart et al, 2010).

In experiments involving constricting the arterial blood supply to rats' hearts, researchers demonstrated a 34% increase in the amount of caveolin-3 produced by the rat's hearts, along with a 27% increase in the weight of the left ventricle, indicating ventricular hypertrophy. What this implies is that the heart needs additional caveolin to cope with blocked vessels, whereas statins interfere with the ability to produce extra caveolin (Kikuchi et al., 2005).

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