http://online.liebertpub.com/doi/abs/10.1089/ars.2013.5524
ABSTRACT
Significance:
The HMG-CoA 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 “over-activity” 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’
anti-atherosclerotic 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.
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