Statins as anti-inflammatory agents in atherogenesis: molecular mechanisms and lessons from the recent clinical trials

Abstract

Ample evidence exists in support of the potent anti-inflammatory properties of statins. In cell studies and animal models statins exert beneficial cardiovascular effects. By inhibiting intracellular isoprenoids formation, statins suppress vascular and myocardial inflammation, favorably modulate vascular and myocardial redox state and improve nitric oxide bioavailability. Randomized clinical trials have demonstrated that further to their lipid lowering effects, statins are useful in the primary and secondary prevention of coronary heart disease (CHD) due to their anti-inflammatory potential. The landmark JUPITER trial suggested that in subjects without CHD, suppression of low-grade inflammation by statins improves clinical outcome. However, recent trials have failed to document any clinical benefit with statins in high risk groups, such in heart failure or chronic kidney disease patients. In this review, we aim to summarize the existing evidence on statins as an anti-inflammatory agent in atherogenesis. We describe the molecular mechanisms responsible for the antiinflammatory effects of statins, as well as clinical data on the non lipid-lowering, anti-inflammatory effects of statins on cardiovascular outcomes. Lastly, the controversy of the recent large randomized clinical trials and the issue of statin withdrawal are also discussed.

Fig. (1)

Statins and nitric oxide bioavailability. Statins favorably affect eNOS gene expression, eNOS mRNA and protein levels and eNOS coupling. By inhibiting intracellular isoprenoids formation, statins reduce the activation of the small GTPase Rho protein, resulting in increased eNOS gene expression via Klf2 and eNOS mRNA stabilization by its polyadenylation. eNOS gene expression is also increased via stimulation of the PI3-Akt pathway by statins. PI3-Akt pathway may be also enhanced by Hsp90 upregulation by statins. Both PI3-Akt and Hsp90 induce eNOS protein phosphorylation at Ser1177 that increases eNOS activity. Caveolin-1 regulates subcellular localization of eNOS and inactivates the enzyme. Statins reduce expression of caveolin-1 and therefore increase cytosolic abundance of eNOS. Intracellular HMG-CoA reductase inhibition by statins increases GCH1 mRNA expression, the gene that encodes GTPCH, the rate limiting enzyme in BH₄ biosynthesis that is critical for eNOS coupling. Statins also indirectly improve eNOS coupling by lowering vascular O₂^- generation. Rac1 inactivation by statins inhibits NADPH-oxidase activity and NAPDH-oxidase derived O₂^- while a direct scavenging of O₂^- by statins has also been reported. O₂^- reduces NO bioavailability by reacting with NO to form ONOO^- the latter being mainly responsible for BH₄ oxidation. Finally, increased DDAH by statins -the enzyme responsible for ADMA catabolism- results in lower ADMA levels and improved eNOS coupling. ADMA: asymmetric dimethylarginine, BH4: tetrahydrobiopterin, DDAH: dimethylarginine dimethylaminohydrolase, eNOS: endothelial nitric oxide synthase, GTPCH: GTP-cyclohydrolase I, HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A, Hsp90: Heat shock protein 90, Klf2: Kruppel-like factor 2, NO: nitric oxide, O₂^-: superoxides, ONOO^-: peroxynitrite, (-): inhibits/suppresses, (+): increases.