Statins have been proposed to exert pleiotropic benefits that extend beyond that predicted by cholesterol reduction (1
), even though some analyses argue against the existence of such non-cholesterol related effects in preventing adverse cardiovascular events (3
). A meta-regression analysis of data from statin and non-statin clinical treatment trials has shown that the changes in LDL cholesterol levels alone are sufficient to account for the decrease in cardiovascular events (3
). However, at the cellular level, statins have potent anti-inflammatory and other beneficial effects on immune, endothelial and smooth muscle cells (2
). At the molecular level, these HMG CoA reductase inhibitors not only decrease cholesterol synthesis but also inhibit the isoprenylation and activation of important intracellular signaling proteins such as RhoA and Ras that can affect pathogenesis (1
). These disparate basic and clinical observations indicate a need for further translational investigations to improve our understanding of statin treatment effects. In this regard, the identification of biomarkers that provide additional information about the therapeutic activities of statins may be helpful.
Various cellular elements and signaling pathways contribute to atherosclerosis, but circulating inflammatory cells play a pivotal role in the initiation and final manifestation of disease (4
). Recent work examining the transcriptional profiles of blood cells in patients with coronary artery disease provide insights into cardiovascular pathogenesis supporting the potential clinical utility of such investigations (6
). We previously reported that the mononuclear cell mRNA level of the Finkel-Biskis-Jinkins Osteosarcoma
) gene, a transcription factor essential for monocyte differentiation into macrophages (9
), was correlated with the severity of atherosclerosis (10
). The localization of FOS
to macrophages and smooth muscle cells in plaques and its importance in calcification suggest that it may also play a direct role in atherosclerosis (10
). Based on the known transcriptional regulation of FOS through a cholesterol-independent pathway (13
), we hypothesized that blood FOS levels will be sensitive to statin treatment independent of LDL cholesterol levels and in a dose dependent manner. The following translational study was designed to determine whether FOS
expression in blood can serve as a statin treatment response marker that could then be evaluated further with regard to clinical application given, for example, the questions about the pleiotropic effects of statins.