Background

Macrophages play a central role in the development of atherosclerosis. However, the signaling pathways that regulate their function are not well understood. The Rho-associated coiled-coil containing kinases (ROCK1 and ROCK2) are serine-threonine protein kinases that are involved in the regulation of the actin cytoskeleton. Recent studies suggest that ROCK1 in macrophages and bone marrow (BM)-derived cells mediates atherogenesis. However, a similar role for ROCK2 in the pathogenesis of atherosclerosis has not been determined.

Methods and Results

The BMs from wild-type (WT), ROCK2+/− and ROCK2−/− mice were transplanted into irradiated recipient LDLr−/− mice and atherosclerosis was induced with a 16-week high-cholesterol diet. Compared to WT BM transplanted (BMT) mice, ROCK2+/− BMT and ROCK2−/− BMT mice showed substantially less lipid accumulation in the aorta (8.46±1.42% and 9.80±2.34% vs. 15.64±1.89%, p< 0.01 for both) and decreased atherosclerotic lesions in the subaortic sinus (158.1±44.4 and 330.1±109.5× 10 3 μm 2 vs. 520.2±125.7× 10 3 μm 2, p< 0.01 for both). These findings correlated with decreased foam cell formation (2.27±0.57 vs. 4.10±0.3, p< 0.01) and increased cholesterol efflux (17.65±0.6 vs. 9.75±0.8, p< 0.05) in ROCK2-deficient mice that are mediated, in part, through the PPARγ-LXR-ABCA-1 pathway in macrophages.

Conclusions

ROCK2 contributes to atherosclerosis, in part, by inhibiting PPARγ-mediated reverse cholesterol transport in macrophages, which contributes to foam cell formation. These findings suggest that inhibition of ROCK2 in macrophages may have therapeutic benefits in preventing the development of atherosclerosis.