Disruption of p21-activated kinase 1 gene diminishes atherosclerosis in apolipoprotein E-deficient mice

Nikhlesh K. Singh; Sivareddy Kotla; Elena Dyukova; James G. Traylor; A. Wayne Orr; Jonathan Chernoff; Tony N. Marion; Gadiparthi N. Rao

doi:10.1038/ncomms8450

Disruption of p21-activated kinase 1 gene diminishes atherosclerosis in apolipoprotein E-deficient mice

Nikhlesh K. Singh, Sivareddy Kotla, Elena Dyukova, James G. Traylor, A. Wayne Orr, Jonathan Chernoff, Tony N. Marion, Gadiparthi N. Rao

Cancer Signaling and Microenvironment (CSM)

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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.

Original language	English
Article number	7450
Pages (from-to)	7450
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms8450
State	Published - Jun 24 2015

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title = "Disruption of p21-activated kinase 1 gene diminishes atherosclerosis in apolipoprotein E-deficient mice",

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.",

author = "Singh, {Nikhlesh K.} and Sivareddy Kotla and Elena Dyukova and Traylor, {James G.} and Orr, {A. Wayne} and Jonathan Chernoff and Marion, {Tony N.} and Rao, {Gadiparthi N.}",

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AU - Singh, Nikhlesh K.

AU - Kotla, Sivareddy

AU - Dyukova, Elena

AU - Traylor, James G.

AU - Orr, A. Wayne

AU - Chernoff, Jonathan

AU - Marion, Tony N.

AU - Rao, Gadiparthi N.

PY - 2015/6/24

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N2 - 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.

AB - 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.

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Disruption of p21-activated kinase 1 gene diminishes atherosclerosis in apolipoprotein E-deficient mice

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