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

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

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 (US)
Article number	7450
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms8450
State	Published - Jun 24 2015
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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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.}",

note = "Funding Information: This work was supported by grants HL103575 and HL069908 to G.N.R. and HL098435 to A.W.O. from the National Heart, Lung and Blood Institute of National Institutes of Health. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited. All rights reserved.",

year = "2015",

month = jun,

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doi = "10.1038/ncomms8450",

language = "English (US)",

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T1 - Disruption of p21-activated kinase 1 gene diminishes atherosclerosis in apolipoprotein E-deficient mice

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.

N1 - Funding Information: This work was supported by grants HL103575 and HL069908 to G.N.R. and HL098435 to A.W.O. from the National Heart, Lung and Blood Institute of National Institutes of Health. Publisher Copyright: © 2015 Macmillan Publishers Limited. All rights reserved.

PY - 2015/6/24

Y1 - 2015/6/24

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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