Regulation of the Endothelial Cytoskeleton by Statins

The primary function of the Rho signaling proteins is regulation of the cytoskeleton. In the endothelium, cytoskeletal filament rearrangement determines barrier function. In response to certain stimuli, such as thrombin, RhoA is activated and localized to the membrane. Rho-kinase is consequently activated, leading to the formation of actin stress fibers, focal adhesions, intercellular gap formations, and disruption of EC barrier function. Simvastatin (5 mM for 16 to 24 hours) attenuates thrombin-induced disruption of barrier function by roughly two thirds in both systemic and pulmonary EC and reduces vascular leakage in hyperlipidemic animals. Morphologically, ECs demonstrate reduced stress fibers at baseline and in response to thrombin (Figure 2).

In addition, we have observed cortical actin ring enhancement associated with increased translocation of cortactin to the cell periphery in statin-treated pulmonary EC that persists after thrombin stimulation. This effect has previously been shown to be mediated by Rac activation through Edg receptor agonists, such as sphingosine 1-phosphate and shear stress. Indeed, statins increase GTP-bound (activated) Rac in whole-cell lysates, whereas membrane-bound Rac is reduced. Prenylation of Rac is required for its attachment to membranes and activation of certain downstream effectors such as NADPH oxidase, but also reduces its binding to Rho-GDI (guanine nucleotide dissociation inhibitor), which normally maintains Rac in its inactive GDP-bound state [5]. Statins may also alter various guanine nucleotide exchange factor proteins (GEPs) or GTPase-activating proteins (GAPs) that positively regulate Rho family activity. Thus, some functions of Rac, such as its effects on cytoskeletal rearrangement, may not require membrane localization and these may be increased in response to statin treatment.

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