Protein Kinase C-β and Oxygen Deprivation

Yan, Shi Fang; Lu, Jiesheng; Zou, Yu; Kisiel, Walter; Mackman, Nigel; Leitges, Michael; Steinberg, Susan F.; Pinsky, David J.; Stern, David M.

doi:10.1074/jbc.275.16.11921

Cited by 54 publications

(17 citation statements)

References 59 publications

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“…We previously reported that PKCβ −/− /ApoE −/− mice displayed less atherosclerosis than ApoE −/− mice and demonstrated links between activation of PKCβ and nondiabetic atherosclerosis. 10 In parallel, our previous findings revealed that activated PKCβ, especially βII isoform, is a critical upstream regulator of early growth response 1 (Egr-1) in response to vascular stress, such as hypoxia, 11, 12 ischemia/reperfusion 13 and nondiabetic atherosclerosis. 10 Egr-1, in turn, acts as a master switch coordinating expression of proinflammatory cytokines, chemokines, procoagulant molecules, cell adhesion molecules, and matrix metalloproteinase-2 (MMP-2).…”

Section: Introductionmentioning

confidence: 62%

“…Consistent with these observations, high glucose-induced increase in Egr-1 transcripts in U937 macrophages was blunted by the inhibitors of PKCβ, ERK1/2 and JNK, but not by the inhibitor of p38. Since Egr-1 has been demonstrated to play an important role in nondiabetic atherosclerosis 15, 30, 31 and it is one of the key downstream target genes of PKCβ and ERK1/2 or JNK in the response to hypoxia, 11, 12, 32 ischemia, 13 acute vascular injury 33, 34 and in nondiabetc atherosclerosis, 10 our current data suggest that PKCβ mediates upregulation of Egr-1, at least in part, via increased phosphorylation of ERK1/2 and JNK in early atherogenesis in diabetes. Furthermore, as there are two putative Egr-1 binding motifs in the proximal region of the CD11c (p150,95) promoter which may participate in the regulation of CD11c expression based on our TRANSFAC database search, 35 we examined the effects of high glucose-stimulated PKCβ-dependent signaling pathway on CD11 gene expression in U937 macrophages.…”

Section: Discussionmentioning

confidence: 99%

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PKCβ Promotes Vascular Inflammation and Acceleration of Atherosclerosis in Diabetic ApoE Null Mice

Kong

Shen²,

Lin³

et al. 2013

ATVB

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Objective Diabetic subjects are at high risk for developing atherosclerosis through a variety of mechanisms. As the metabolism of glucose results in production of activators of protein kinase C (PKC)β, it was logical to investigate the role of PKCβ in modulation of atherosclerosis in diabetes. Approach and Results ApoE−/− and PKCβ −/−/ApoE−/− mice were rendered diabetic with streptozotocin. Quantification of atherosclerosis, gene expression profiling or analysis of signaling molecules was performed on aortic sinus or aortas from diabetic mice. Diabetes-accelerated atherosclerosis increased the level of phosphorylated ERK1/2 and JNK mitogen activated protein (MAP) kinases and augmented vascular expression of inflammatory mediators, as well as increased monocyte/macrophage infiltration and CD11c+ cells accumulation in diabetic ApoE−/− mice; processes which were diminished in diabetic PKCβ −/−/ApoE−/− mice. In addition, pharmacological inhibition of PKCβ reduced atherosclerotic lesion size in diabetic ApoE−/− mice. In vitro, the inhibitors of PKCβ and ERK1/2, as well as small interfering RNA (siRNA) to Egr-1 significantly decreased high glucose-induced expression of CD11c (Itgax), chemokine (C-C motif) ligand 2 (CCL2) and interleukin (IL)-1β in U937 macrophages. Conclusions These data link enhanced activation of PKCβ to accelerated diabetic atherosclerosis via a mechanism that includes modulation of gene transcription and signal transduction in the vascular wall; processes that contribute to acceleration of vascular inflammation and atherosclerosis in diabetes. Our results uncover a novel role for PKCβ in modulating CD11c expression and inflammatory response of macrophages in the development of diabetic atherosclerosis. These findings support PKCβ activation as a potential therapeutic target for prevention and treatment of diabetic atherosclerosis.

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Section: Introductionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

PKCβ Promotes Vascular Inflammation and Acceleration of Atherosclerosis in Diabetic ApoE Null Mice

Kong

Shen²,

Lin³

et al. 2013

ATVB

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“…A cascade of events leading from Hmox-1 induction to CO generation, through an intermediary step of ERK phosphorylation, represses the Egr-1 ''master switch'' (12). Induction of Egr-1 by hypoxia (19) or ischemia (12) triggers procoagulant and inflammatory genes (12,13,19,26) such as TF, serpine-1, and IL-1␤. Modulation of these genes by CO (5, 10) may contribute to its clinically beneficial actions in lung transplantation (27).…”

Section: Discussionmentioning

confidence: 99%

Carbon monoxide rescues ischemic lungs by interrupting MAPK-driven expression of early growth response 1 gene and its downstream target genes

Mishra

Fujita

Lama

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Carbon monoxide (CO), an endogenous cytoprotective product of heme oxygenase type-1 regulates target thrombotic and inflammatory genes in ischemic stress. Regulation of the gene encoding early growth response 1 (Egr-1), a potent transcriptional activator of deleterious thrombotic and inflammatory cascades, may govern CO-mediated ischemic lung protection. The exact signaling mechanisms underlying CO-mediated cytoprotection are not well understood. In this study we tested the hypothesis that inhibition of mitogen-activated protein kinase-dependent Egr-1 expression may be pivotal in CO-mediated ischemic protection. In an in vivo isogeneic rat lung ischemic injury model, inhaled CO not only diminished fibrin accumulation and leukostasis and improved gas exchange and survival but also suppressed extracellular signalregulated kinase (ERK) activation, Egr-1 expression, and Erg DNAbinding activity in lung tissue. Additionally, CO-mediated inhibition of Egr-1 reduced expression of target genes, such as tissue factor, serpine-1, interleukin-1, and TNF-␣. However, CO failed to inhibit serpine-1 expression after unilateral lung ischemia in mice null for the Egr-1 gene. In RAW macrophages in vitro, hypoxiainduced Egr-1 mRNA expression was ERK-dependent, and COmediated suppression of ERK activation resulted in Egr-1 inhibition. Furthermore, CO suppression of ERK phosphorylation was reversed by the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one but was insensitive to cAMP-dependent protein kinase A inhibition with H89 and NO synthase inhibition with L-nitroarginine methyl ester. This finding indicates that CO suppresses ERK in a cGMP-dependent but cAMP͞protein kinase A-and NO-independent manner. Together, these data identify a unifying molecular mechanism by which CO interrupts proinflammatory and prothrombotic mediators of ischemic injury.

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“…The stimulation of cells with AGEs has been shown to produce reactive oxygen species (56). Moreover, at high concentrations (1 mg/ml) HGA could induce NF-B activation (18).…”

Section: Figmentioning

confidence: 99%

Human Glycated Albumin Affects Glucose Metabolism in L6 Skeletal Muscle Cells by Impairing Insulin-induced Insulin Receptor Substrate (IRS) Signaling through a Protein Kinase Cα-mediated Mechanism

Miele

Riboulet

Maitan

et al. 2003

Journal of Biological Chemistry

130

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Nonenzymatic glycation is increased in diabetes and leads to increased levels of glycated proteins. Most studies have focused on the role of glycation products in vascular complications. Here, we have investigated the action of human glycated albumin (HGA) on insulin signaling in L6 skeletal muscle cells. Exposure of these cells to HGA inhibited insulin-stimulated glucose uptake and glycogen synthase activity by 95 and 80%, respectively. These effects were time-and dose-dependent, reaching a maximum after 12 h incubation with 0.1 mg/ml HGA. In contrast, exposure of the cells to HGA had no effect on thymidine incorporation. Further, HGA reduced insulin-stimulated serine phosphorylation of PKB and GSK3, but did not alter ERK1/2 activation. HGA did not affect either insulin receptor kinase activity or insulin-induced Shc phosphorylation on tyrosine. In contrast, insulin-dependent IRS-1 and IRS-2 tyrosine phosphorylation was severely reduced in cells preincubated with HGA for 24 h. Insulin-stimulated association of PI3K with IRS-1 and IRS-2, and PI3K activity were reduced by HGA in parallel with the changes in IRS tyrosine phosphorylation, while Grb2-IRS association was unchanged. In L6 myotubes, exposure to HGA increased PKC activity by 2-fold resulting in a similar increase in Ser/Thr phosphorylation of IRS-1 and IRS-2. These phosphorylations were blocked by the PKC inhibitor bisindolylmaleimide (BDM). BDM also blocked the action of HGA on insulin-stimulated PKB and GSK3␣. Simultaneously, BDM rescued insulin-stimulation of glucose uptake and glycogen synthase activity in cells exposed to HGA. The use of antibodies specific to PKC isoforms shows that this effect appears to be mediated by activated PKC␣, independent of reactive oxygen species production. In summary, in L6 skeletal muscle cells, exposure to HGA leads to insulin resistance selectively in glucose metabolism with no effect on growth-related pathways regulated by the hormone.

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Protein Kinase C-β and Oxygen Deprivation

Cited by 54 publications

References 59 publications

PKCβ Promotes Vascular Inflammation and Acceleration of Atherosclerosis in Diabetic ApoE Null Mice

PKCβ Promotes Vascular Inflammation and Acceleration of Atherosclerosis in Diabetic ApoE Null Mice

Carbon monoxide rescues ischemic lungs by interrupting MAPK-driven expression of early growth response 1 gene and its downstream target genes

Human Glycated Albumin Affects Glucose Metabolism in L6 Skeletal Muscle Cells by Impairing Insulin-induced Insulin Receptor Substrate (IRS) Signaling through a Protein Kinase Cα-mediated Mechanism

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