Abstract
Pak1 plays an important role in various cellular processes, including cell motility, polarity, survival and proliferation. To date, its role in atherogenesis has not been explored. Here we report the effect of Pak1 on atherogenesis using atherosclerosis-prone apolipoprotein E-deficient (ApoE−/−) mice as a model. Disruption of Pak1 in ApoE−/− mice results in reduced plaque burden, significantly attenuates circulating IL-6 and MCP-1 levels, limits the expression of adhesion molecules and diminishes the macrophage content in the aortic root of ApoE−/− mice. We also observed reduced oxidized LDL uptake and increased cholesterol efflux by macrophages and smooth muscle cells of ApoE−/−:Pak1−/− mice as compared with ApoE−/− mice. In addition, we detect increased Pak1 phosphorylation in human atherosclerotic arteries, suggesting its role in human atherogenesis. Altogether, these results identify Pak1 as an important factor in the initiation and progression of atherogenesis.
Highlights
p21-Activated kinases (Paks)[1] plays an important role in various cellular processes, including cell motility, polarity, survival and proliferation
We observed a decrease in the plasma levels of IL-6 and monocyte chemoattractant protein (MCP)-1 in ApoE À / À : Pak[1] À / À mice as compared with that in ApoE À / À mice and these levels correlated with its decreased expression both in macrophages and SMCs of these mice
As increased migration and proliferation capacities are the characteristic features of dedifferentiated SMC phenotype[40], the decreased migration of SMC from Western diet (WD)-fed ApoE À / À :Pak[1] À / À mice as compared with SMC of ApoE À / À mice may infer that Pak[1] plays a role in SMC phenotype switching during atherogenesis
Summary
Pak[1] plays an important role in various cellular processes, including cell motility, polarity, survival and proliferation. A study has demonstrated that Pak[1] mediates activation of inflammatory signalling events in endothelial cells[17] The latter observations may infer that Pak[1] might be playing a role in the pathogenesis of atherosclerosis, but to date the contribution of Pak[1] in atherogenesis is unknown. Macrophage content, decreased cluster of differentiation 36 (CD36) levels with reduced oxidized low-density lipoprotein (OxLDL) uptake and increased ABCA1 levels with enhanced cholesterol efflux by both peritoneal macrophages and VSMCs, leading to a reduction in plaque burden in ApoE À / À mice Together, these findings demonstrate that Pak[1] plays a crucial role in the pathogenesis of atherosclerosis
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