Cholesterol-independent benefits of statins in cardiac hypertrophy

The statin drugs are best known for their ability to block cholesterol biosynthesis and have been widely prescribed to people at risk of heart disease because of high serum cholesterol. Takemoto and coworkers have now identified another beneficial effect of these drugs that might make them suitable for treating a different set of heart patients, those with cardiac hypertrophy. The hypertrophic response in cardiac myocytes entails not just an increase in cell size, but also a reversion to a pattern of gene expression normally seen only in early heart development. Statins, which block mevalonate biosynthesis, prevent cells from producing a variety of this lipid?s metabolites, including some that become covalently linked to important regulatory proteins. Small, GTP-binding proteins of the Rho family, particularly Rac1, are lipid-modified and play a crucial role in remodeling the actin cytoskeleton when cells move or change shape. Takemoto et al. confirm here that lipid-linked Rac1 is also key to the hypertrophic response, and they show that reactive oxygen species, formed specifically in cells with an active and properly localized Rac1 protein, drive myocyte hypertrophy, both in living animals and in cells. The antioxidant effect of the statins, mediated by Rac, is independent of its effects as a cholesterol lowering agent, since the anti-hypertrophic effect occurs even when cholesterol is restored to the cells.

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