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Bisphosphonates may retrieve endothelial function in vascular diseases similar to statins’ effects

To the Editor: We read the article by Koizumi et al. on the apoptotic effects and possible mechanisms of zoledronate (ZOL) in dexamethasone-resistant multiple myeloma cells (Dex-R) with great interest (1). They concluded that ZOL reduced the viability and induced apoptosis of Dex-R cells by inducing actin fiber rearrangement and unprenylating portions of the small G proteins. These results are consistent with our previous studies (2). The authors demostrated that inhibition of farnesylpyrophosphate (FPP) synthase by ZOL results in reduced production of isoprenoid intermediates like geranylgeranylpyrophosphate (GGPP) and FPP. They observed that the addition of geranylgeraniol (GGOH), which is essential for geranylgeranylation and for membrane attachment of small GTP-binding proteins such as Rho and Rap1A, inhibited the viability-suppressing, apoptotic and actin fiber-disrupting effects of ZOL. Authors’ these important and novel findings raise the possibility that pleitropic effects of bisphosphonates can be attributed to their effects on mevalonate pathway which is also important in the regulation of endothelial function (Fig. 1). Endothelial dysfunction is associated with vascular diseases may result from impairment of the synthesis, release, or activity of endothelium-derived vasorelaxing factors including nitric oxide (NO). Endothelium-derived NO inhibits several components of the atherogenic process including monocyte adhesion to the endothelial surface, platelet aggregation, vascular smooth muscle cell proliferation, and vasoconstriction. Therefore, the NO production within the endothelium is served as a target system in the treatment of endothelial dysfunction associated with the vascular diseases. The possible role of RhoA-Rho-kinase system in the regulation of endothelial NO was provided by the observation that RhoA can negatively regulate eNOS (endothelial NO synthase) mRNA expression in human cultured endothelial cells (3). Therefore, Rho-kinase might inhibit NO production within the endothelium, and thus excessive endothelial Rho-kinase activity might also contribute to endothelial dysfunction and atherosclerosis. In mevalonate pathway, inhibition of 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase by statins, widely used to lower elevated plasma cholesterol levels, not only reduces plasma cholesterol levels, but also decreases intracellular levels of isoprenoid intermediates. Therefore, the protective effects of statins on the endothelium can be attributed the rapid restoration of NO bioactivity by upregulation and activation of eNOS and the enhancement of NO release by inhibiting of