Might the beneficial effects of statin drugs be related to their action on iron metabolism?

Abstract

Although the cholesterol-heart hypothesis is often regarded as a dogmatic belief, controversy continues to surround the aetiology and pathogenesis of atherosclerosis. In fact, lowering cholesterol with statin drugs has been shown to reduce cardiovascular risk. However, statins have pleiotropic effects independent of their capacity to lower cholesterol. We highlight that statin drugs exert an important action on iron metabolism, which in turn may prevent progression and destabilization of atherosclerotic plaque. If it is found that the effect of statins on iron metabolism is a mechanism of their beneficial action, this consequence of statin use can be clinically replicated by other methods, such as controlled reduction of body iron stores. This might allow the use of lower doses or even obviate the use of statins in primary cardiovascular prevention, and therefore avoid the side effects and expense of these drugs.

Iron-Induced Damage in Cardiomyopathy: Oxidative-Dependent and Independent Mechanisms

“…Statin drugs have pleiotropic effects independent of their capacity to lower cholesterol. In particular, it has been shown that they influence the expression of proteins of iron metabolism like heme oxygenase and hepcidin (discussed by [ 46 ]). Further studies are needed to assess the usefulness of statins for the prevention of iron-mediated cardiotoxicity.…”

Why do statins reduce cardiovascular disease more than other lipid modulating therapies?

“…Statins acting directly via anti‐inflammatory pathways is inconsistent with different effects on two inflammatory‐related conditions, that is cardiovascular disease and diabetes. Finally, testosterone suppresses hepcidin explaining a relation with iron metabolism . Statins have been hypothesized to act as a vitamin D analogue , but trials to date do not indicate that vitamin D prevents cardiovascular disease .…”

Deferoxamine stimulates LDLR expression and LDL uptake in HepG2 cells

“…The observation that the upregulation of LDLR by DFO was SREBP independent and so distinct from statins suggests that DFO may serve as a supplement to statins treatment for hypercholesterolemia. Interestingly, a link between statins and iron led to the suggestion that the action of statins on iron metabolism may contribute to their beneficial effect , and also that iron reduction may provide an alternative to statin therapy . Finally, it was reported that several antioxidant compounds such as berberine , quercetin , resveratrol , curcumin , alginate oligosaccharide , or quercetin‐3‐glucoside have the ability to increase LDLR expression, and thus represent anticholesterolemic agents.…”