Effects of Statins on the Microvasculature

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Enhanced eNOS Activity

Nitric oxide (NO) generated by the enzyme NO synthase III (eNOS) constitutively expressed in EC plays a major role in the maintenance of adequate perfusion within the microcirculation. eNOS activity is enhanced in response to shear stress in the precapillary arterioles, mediating VSMC relaxation and increased blood flow. NO also has potent antiplatelet properties and inhibits leukocyte-endothelial cell adhesion, particularly in postcapillary venules, thereby maintaining blood flow.

Statins increase EC eNOS protein levels in a time- and concentration-dependent manner. As little as 0.1 |mmol/L of simvastatin induces a nearly twofold increase in eNOS expression after 48 hours. A post-transcriptional mechanism is involved since eNOS mRNA stability increases without changes in gene transcription. Statins prevent the downregu-lation of eNOS induced by hypoxia and oxidized LDL. These effects are reversed by provision of either mevalonate or GGPP. Statin treatment also rapidly (within 1 hour)

enhances NO production by endothelial cells without necessarily affecting eNOS protein levels [3]. This increase in eNOS activity is mediated by phosphorylation of eNOS at Ser1177, which in turn is dependent on statin-induced eNOS association with the chaperone Hsp 90 and activation of the protein kinase Akt/PKB. Statin treatment also reduces caveolin abundance and the consequent inhibitory effect on eNOS.

Effects on iNOS

The role of inducible NOS II (iNOS) in the microcirculation is controversial. Whereas large quantities of NO contribute to hypotension in septic shock and can induce nitrosative tissue damage, there is evidence that iNOS-derived NO attenuates leukocyte-endothelial adhesion. Statins (1-10 mM) enhance cytokine-mediated induction of iNOS in VSMC and perhaps other cell types. In contrast, reduced iNOS induction by cytokines is noted in EC and macrophages.

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