G protein-coupled receptor kinase-5 attenuates atherosclerosis by regulating receptor tyrosine kinases and 7-transmembrane receptors.

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2012-02

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Abstract

Objective

G protein-coupled receptor kinase-5 (GRK5) is a widely expressed Ser/Thr kinase that regulates several atherogenic receptors and may activate or inhibit nuclear factor-κB (NF-κB). This study sought to determine whether and by what mechanisms GRK5 affects atherosclerosis.

Methods and results

Grk5(-/-)/Apoe(-/-) mice developed 50% greater aortic atherosclerosis than Apoe(-/-) mice and demonstrated greater proliferation of macrophages and smooth muscle cells (SMCs) in atherosclerotic lesions. In Apoe(-/-) mice, carotid interposition grafts from Grk5(-/-) mice demonstrated greater upregulation of cell adhesion molecules than grafts from wild-type mice and, subsequently, more atherosclerosis. By comparing Grk5(-/-) with wild-type cells, we found that GRK5 desensitized 2 key atherogenic receptor tyrosine kinases: the platelet-derived growth factor receptor-β in SMCs, by augmenting ubiquitination/degradation; and the colony-stimulating factor-1 receptor (CSF-1R) in macrophages, by reducing CSF-1-induced tyrosyl phosphorylation. GRK5 activity in monocytes also reduced migration promoted by the 7-transmembrane receptor for monocyte chemoattractant protein-1 CC chemokine receptor-2. Whereas GRK5 diminished NF-κB-dependent gene expression in SMCs and endothelial cells, it had no effect on NF-κB activity in macrophages.

Conclusions

GRK5 attenuates atherosclerosis through multiple cell type-specific mechanisms, including reduction of SMC and endothelial cell NF-κB activity and desensitization of receptor-specific signaling through the monocyte CC chemokine receptor-2, macrophage CSF-1R, and the SMC platelet-derived growth factor receptor-β.

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Muscle, Smooth, Vascular, Endothelium, Vascular, Cells, Cultured, Animals, Mice, Inbred C57BL, Mice, Knockout, Mice, Disease Models, Animal, Receptor, Macrophage Colony-Stimulating Factor, Receptor, Platelet-Derived Growth Factor beta, Apolipoproteins E, NF-kappa B, Receptors, Tumor Necrosis Factor, Type I, Signal Transduction, Cell Proliferation, Cell Movement, Male, Atherosclerosis, Toll-Like Receptor 4, Receptors, CCR2, G-Protein-Coupled Receptor Kinase 5

Citation

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https://hdl.handle.net/10161/31549

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https://creativecommons.org/licenses/by-nc/4.0

Published Version (Please cite this version)

10.1161/atvbaha.111.239608

Publication Info

Wu, Jiao-Hui, Lisheng Zhang, Alexander C Fanaroff, Xinjiang Cai, Krishn C Sharma, Leigh Brian, Sabrina T Exum, Sudha K Shenoy, et al. (2012). G protein-coupled receptor kinase-5 attenuates atherosclerosis by regulating receptor tyrosine kinases and 7-transmembrane receptors. Arteriosclerosis, thrombosis, and vascular biology, 32(2). pp. 308–316. 10.1161/atvbaha.111.239608 Retrieved from https://hdl.handle.net/10161/31549.

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Zhang

Lisheng Zhang

Assistant Professor in Medicine

My research efforts involves studying the pathogenesis of vein graft neointimal hyperplasia and atherosclerosis.
The greatest amount of my time in the past years has been devoted to developing and characterizing our interposition vein graft model in mice. This model allows us to use IVC to carotid artery transplants between congenic mice. These transplants allow us to ask the questions about which gene products contribute to the pathogenesis of vein graft disease. In addition, I have used carotid artery to carotid artery transplants to study the role of TNF receptors in atherosclerosis. For these studies, we have used apolipoprotein E-deficient mice as graft recipients.
By using mouse vein graft model we demonstrate that most of the neointimal cells in vein grafts originate from cellular pools outside of the vein graft at the time of its implantation. The importance of this work relates to our persistent inability to treat vein graft disease in human beings. The second work demonstrates that expression of the tumor necrosis factor receptor-1, even in just in the vein graft cells themselves, contributes to the pathogenesis of vein graft neointimal hyperplasia. In this project, I surgically created chimeric mice to demonstrate molecular mechanisms by which the tumor necrosis factor receptor-1 aggravates neointimal hyperplasia, a process that is believed to lay the foundation for accelerated atherosclerosis in vein grafts.
I have also adapted my vein graft procedure in mice to ask questions about the arterial wall’s role in atherosclerosis. This atherosclerosis model involves making carotid interposition grafts not with veins, but with the carotid artery of congenic mice, and placing them into the carotid artery of spontaneously atherogenic mice that are deficient in apolipoprotein E.
I plan to continue our studies related to the role of inflammatory cytokine receptors in neointimal hyperplasia and atherosclerosis. In addition, I envision extending this work with the surgical models I have created in mice.

Shenoy

Sudha Kaup Shenoy

Professor in Medicine

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