Abstract 306: Deficiency of ROCK1 in Macrophages Protects Against Atherosclerosis
Background: Rho kinases (ROCKs) are serine-threonine protein kinases that regulate various cellular functions. There is increasing evidence that the RhoA/ROCK pathway plays an important pathophysiological role in cardiovascular diseases. However, direct evidence of which ROCK isoforms or target tissues are involved in the atherogenic process is still lacking.
Objective: The aim of this study was to determine the effect of ROCK1 deficiency on atherogenesis and how ROCK1 affects key atherosclerosis-related macrophage function such as lipid uptake and chemotaxis.
Methods: We utilized ROCK1−/− mice and the atherosclerosis-prone apolipoprotein E knockout (apoE−/−) mice or low-density lipoprotein receptor knockout (LDLR−/−) mice to investigate the role of ROCK1 in the pathogenesis of atherosclerotic plaque formation. Bone marrow-derived macrophages from ROCK1−/− and ROCK1+/+ mice were used to investigate acetylated (Ac)LDL-mediated foam cell formation and chemotaxis.
Results: Compared to atherosclerosis-prone apoE−/− mice, apoE−/− ROCK1+/− mice had substantially less fatty streaks foam cells and atherosclerosis (77.0 ± 12.9 × 103 μm2 versus 166.4 ± 14.6 × 103 μm2, P < 0.01). Atherosclerotic lesions were reduced also in LDLR−/− mice, whose bone marrow were replaced with bone marrow derived from ROCK1−/− mice compared to ROCK1+/+ recipients (181.5 ± 15.6 × 103 μm2 versus 448.5 ± 33.3 × 103 μm2, P < 0.05). Bone marrow-derived ROCK1-deficient macrophages exhibited impaired chemotaxis to monocyte chemotactic protein-1 and showed reduced ability to take up lipids and to develop into foam cells when exposed to modified low density lipoprotein.
Conclusion: These findings indicate that ROCK1 in macrophages is a critical mediator of foam cell formation, macrophage chemotaxis and atherogenesis, and suggest that macrophage ROCK1 may be an important therapeutic target for vascular inflammation and atherosclerosis.