Reduction of serum C-reactive protein by statin therapy may reflect decreased isoprenylation of Rac-1, a mediator of the IL-6 signal transduction pathway.
Recent studies demonstrate that statin therapy decreases plasma levels of C-reactive protein (CRP), a potent risk factor for thrombotic vascular events. CRP is an acute phase reactant, and most circulating CRP is synthesized by hepatocytes in response to IL-6. Since statins do not appear to have a consistent impact on serum levels of IL-6, their impact on plasma CRP very likely reflects down-regulation of hepatocyte responsiveness to this cytokine. The ability of IL-6 to promote transcription of CRP is mediated, in large part, by activation of the transcription factor STAT3; this activation requires both a tyrosine phosphorylation (mediated by the IL-6 receptor complex) and a serine phosphorylation (Ser-727), the origin of which has been more obscure. There is new evidence that, when hepatocytes are exposed to IL-6, the consequent serine phosphorylation of STATS is mediated by a signal transduction pathway in which the G-protein Rac-1 plays an obligate role. Inasmuch as the proper function of Rac-1 is contingent on isoprenylation that anchors it to the plasma membrane, it is reasonable to hypothesize that statin therapy interferes with IL-6 signaling in hepatocytes by suppressing the isoprenylation of Rac-1; a decrease in the transcription of CRP would be a likely consequence of this effect. Whether or not a reduction in elevated CRP is directly beneficial to vascular health, statins can exert direct effects on vascular endothelial function that should help prevent vascular inflammation and thrombosis, and thus should be of particular benefit to subjects - such as those with high CRP levels - who are at high risk for vascular events.
McCarty
Mark F
MF
Pantox Laboratories, San Diego, California, USA.
D002097:C-Reactive Protein / Q000378:metabolism*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism*; D017368:Protein Prenylation; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D000960:Hypolipidemic Agents; D015850:Interleukin-6; D002097:C-Reactive Protein; D020830:rac1 GTP-Binding Protein