Statins and Modulation of Oxidative Stress

Abstract

Statins inhibit the activity of a rate-limiting enzyme in cholesterol biosynthesis, converting 3-hydroxy 3-methylglutaryl coenzyme A to mevalonate, and are widely used in the treatment of cardiovascular diseases. Statins decrease the synthesis of cholesterol and other nonsteroid isoprenoids originating from mevalonate, such as farnesyl- and geranylgeranylpyrophosphate, dolichol, and ubiquinone. Recent studies indicate that the beneficial effect of statins on cardiovascular risk also occurs in persons with normal plasma cholesterol because of the pleiotropic cholesterol-independent activities of statins. Among these effects, modulation of oxidative stress is one of the most important. Statins reduce the generation of reactive oxygen species by vascular NAD(P)H oxidase, inhibit the respiratory burst of phagocytes, antagonize the prooxidant effect of angiotensin II and endothelin-1, and increase the synthesis of vascular nitric oxide. Some statins and their metabolites posses direct free radical scavenging activity. The antioxidant effect of statins contributes to inhibition of atherogenesis, stabilization of atherosclerotic plaque, inhibition of myocardial hypertrophy and remodeling, and modulation of vascular tone. However, the prooxidant effect of statins resulting from the inhibition of ubiquinone synthesis has also been reported in some experimental models. This effect may contribute to side effects of statins, such as myopathy and hepatotoxicity.

Atorvastatin treatment affects atrial ion currents and their tachycardia-induced remodeling in rabbits

“…In this model, the balance of oxidized/ reduced form of glutathione influenced I to current density (Rozanski and Xu 2002). As statins are also able to affect this equilibrium (Beltowski 2005), a statin-induced shift of cellular redox state might finally also alter I to in our model.…”

Cytokine alterations and cognitive impairment in major depressive disorder: From putative mechanisms to novel treatment targets

“…Importantly, statins are able to pass through BBB and exert a number of pleiotropic activities that might underlie their antidepressant efficacy. It has been found that statins increase the availability of tryptophan by inhibiting IDO (Kilic et al, 2012) and exert antioxidant properties (Beltowski, 2005). Additionally, statins might be involved in inflammatory processes (Antonopoulos et al, 2012).…”

A comparative study on the antimutagenicity of atorvastatin and lovastatin against directly acting mutagens

“…Many chemopreventive agents appear to target signaling intermediates in apoptosis-inducing pathways (Sun et al, 2004) and are found to be antioxidant (Giacosa et al, 1997). Lovastatin has been reported to possess proapoptotic (Chan et al, 2003) and antioxidant activities (Beltowski, 2005). Hence the demonstrated antimutagenic activity of lovastatin and atorvastatin supports their possible therapeutic application as cancer chemopreventive agents.…”