Glycogen Synthase Kinase 3α Deficiency Attenuates Atherosclerosis and Hepatic Steatosis in High Fat Diet–Fed Low Density Lipoprotein Receptor–Deficient Mice

Banko, Nicole; McAlpine, Cameron S.; Venegas-Pino, Daniel E.; Raja, Preeya; Shi, Yuanyuan; Khan, Mohammad Ibrahim; Werstuck, Geoff H.

doi:10.1016/j.ajpath.2014.07.028

Cited by 24 publications

(28 citation statements)

References 41 publications

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“…In mouse models, pharmacological inhibition of GSK3α/β or whole-body GSK3α deletion attenuates atherosclerotic lesion formation and the development of hepatic steatosis. [19][20][21] Although suggestive of a role for GSK3α/β in atherosclerosis, the homolog-and tissue-specific functions of GSK3α and GSK3β, as well as the mechanism by which GSK3α/β regulates atherosclerosis, are not known.…”

Section: Arterioscler Thromb Vasc Biolmentioning

confidence: 99%

“…12,19,20,24 However, the homolog-specific functions of GSK3α and GSK3β in hepatic lipid metabolism have not been determined. Therefore, we analyzed lipid metabolism in the liver of HFD-fed LLαKO and LLβKO mice.…”

Section: Hepatic Gsk3α or Gsk3β Deletion Does Not Affect Hepatic Lipimentioning

confidence: 99%

“…[13][14][15] Wholebody GSK3α-deficient mice are viable and develop normally, whereas GSK3β deletion is embryonically lethal. [16][17][18][19] Recent evidence has suggested a role of GSK3α/β in atherosclerosis. In mouse models, pharmacological inhibition of GSK3α/β or whole-body GSK3α deletion attenuates atherosclerotic lesion formation and the development of hepatic steatosis.…”

Section: Arterioscler Thromb Vasc Biolmentioning

confidence: 99%

“…After 10 weeks of HFD feeding, myeloid cell ablation of GSK3α did not significantly alter plasma cholesterol, triglyceride, or glucose concentrations or affect liver or adipose weight (Table 2) GSK3α/β plays a role in the regulation of inflammatory cytokine expression. 19,25,26 To investigate this further, we analyzed the plasma cytokine profile in LMαKO mice. After 10 weeks of HFD, LMαKO mice displayed reduced plasma levels of the proinflammatory cytokines IL-6 and tumor necrosis factor-α, and increased plasma levels of the anti-inflammatory cytokine IL-10 ( Figure 3E).…”

Section: Myeloid Gsk3α Deletion Attenuates Atherosclerosismentioning

confidence: 99%

“…GSK3α −/− mice were used for bone marrow transplantation experiments. 16,19 Briefly, 5-week-old recipient mice were irradiated and then injected with bone marrow (3×10 6 cells) from donor mice. Recipient mice were then fed a HFD for 10 weeks.…”

Section: Micementioning

confidence: 99%

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Deletion of Myeloid GSK3α Attenuates Atherosclerosis and Promotes an M2 Macrophage Phenotype

McAlpine

Huang

Emdin

et al. 2015

ATVB

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A therosclerosis is the main underlying pathology of cardiovascular disease, which accounts for the majority of deaths in developed nations.1 Myeloid lineage cells are critical mediators in the development of atherosclerosis and account for the majority of a lesion's cellular bulk.2 Within the atherosclerotic lesion, macrophages phagocytose modified lipid particles becoming lipid engorged foam cells. Foam cells exacerbate disease progression through the secretion of proinflammatory cytokines and growth factors. In advanced lesions, foam cells undergo apoptosis leading to the formation of a lipid-rich, acellular, and highly thrombotic necrotic core. The underlying molecular mechanisms that regulate myeloid cell behavior during atherosclerosis remain poorly defined.Increasing evidence suggests that myeloid cell subpopulations are heterogeneous and have distinctive phenotypes that play unique roles in disease states. Macrophages are often broadly classified as having a classical (M1) or an alternative (M2) phenotype. M1 macrophages, elicited by toll-like receptor or interferon-γ receptor stimulation, are the most prominent macrophages at sites of inflammation and exacerbate the inflammatory response through the secretion of proinflammatory cytokines and chemoatractants.3,4 M1 macrophages promote atherosclerotic lesion development and complexity.5-7 M2 macrophages patrol tissue, perform reparative and immunoregulatory functions, efferocytose debris, and are antiatherogenic. 3,4,8 Other macrophage subtypes have been identified in atherosclerotic lesions, including M4, Mox, and Mhem; however, their roles are less well characterized. 3,5,9,10 Our understanding of the cellular signaling networks that regulate macrophage polarization in the context of atherosclerosis and the relative contribution of each phenotype to the progression and development of atherosclerosis is limited.Glycogen synthase kinase (GSK)-3 α and β are homologous serine/threonine kinases encoded by separate genes. 11GSK3α and GSK3β share 98% amino acid homology within their kinase domain but only 36% homology in the C-terminal domain. GSK3α (51 kDa) is 5 kDa larger than GSK3β (46 kDa) because of an N-terminal glycine-rich domain with an © 2015 American Heart Association, Inc. Objective-Glycogen synthase kinase (GSK)-3α/β has been implicated in the pathogenesis of diabetes mellitus, cancer, Alzheimer, and atherosclerosis. The tissue-and homolog-specific functions of GSK3α and β in atherosclerosis are unknown. This study examines the effect of hepatocyte or myeloid cell deletion of GSK3α or GSK3β on atherosclerosis in low-density lipoprotein receptor (LDLR) −/− mice. Approach and Results-We ablated GSK3α or GSK3β expression in hepatic or myeloid cells of LDLR −/− mice, and mice were fed a high-fat diet for 10 weeks. GSK3α or GSK3β deficiency in hepatic or myeloid cells did not affect metabolic parameters, including plasma lipid levels. Hepatic deletion of GSK3α or GSK3β did not affect the development of atherosclerosis or hepatic lipid content. Myeloid ...

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Section: Arterioscler Thromb Vasc Biolmentioning

confidence: 99%