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.