SIGNIFICANCE: The 3-hydroxy-methylglutaryl coenzyme A reductase inhibitors or 
statins are important therapeutic agents for lowering serum cholesterol levels. 
However, recent studies suggest that statins may exert atheroprotective effects 
beyond cholesterol lowering. These so-called "pleiotropic effects" include 
effects of statins on vascular and inflammatory cells. Thus, it is important to 
understand whether other signaling pathways that are involved in atherosclerosis 
could be targets of statins, and if so, whether individuals with "overactivity" 
of these pathways could benefit from statin therapy, regardless of serum 
cholesterol level.
RECENT ADVANCES: Statins inhibit the synthesis of isoprenoids, which are 
important for the function of the Rho/Rho-associated coiled-coil containing 
kinase (ROCK) pathway. Indeed, recent studies suggest that inhibition of the 
Rho/ROCK pathway by statins could lead to improved endothelial function and 
decreased vascular inflammation and atherosclerosis. Thus, the Rho/ROCK pathway 
has emerged as an important target of statin therapy for reducing 
atherosclerosis and possibly cardiovascular disease.
CRITICAL ISSUES: Because atherosclerosis is both a lipid and an inflammatory 
disease, it is important to understand how inhibition of Rho/ROCK pathway could 
contribute to statins' antiatherosclerotic effects.
FUTURE DIRECTIONS: The role of ROCKs (ROCK1 and ROCK2) in endothelial, smooth 
muscle, and inflammatory cells needs to be determined in the context of 
atherogenesis. This could lead to the development of specific ROCK1 or ROCK2 
inhibitors, which could have greater therapeutic benefits with less toxicity. 
Also, clinical trials will need to be performed to determine whether inhibition 
of ROCKs, with and without statins, could lead to further reduction in 
atherosclerosis and cardiovascular disease.