Protein Kinase C θ Activation Induces Insulin-Mediated Constriction of Muscle Resistance Arteries

Bakker, Wineke; Sipkema, Pieter; Stehouwer, Coen D. A.; Serné, Erik H.; Smulders, Yvo M.; Hinsbergh, Victor W.M. van; Eringa, Etto C.

doi:10.2337/db07-0792

Cited by 60 publications

(49 citation statements)

References 52 publications

(59 reference statements)

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“…It is also expressed in natural killer cells 39 ; in platelets, where it may modulate activation and thrombus formation 40 ; in skeletal muscle cells 41 ; in the endothelium of muscle resistance arteries, where it modulates vascular tone through insulin-induced vasoconstriction 42 ; and in hypothalamus tissue, where it contributes to insulin signaling. 43 PKC-could, therefore, exert multifold influence on development of CM, through platelet activation and vascular tone modulation, beyond a direct effect on T cells.…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase C-Theta Is Required for Development of Experimental Cerebral Malaria

Fauconnier

Bourigault

Même

et al. 2011

The American Journal of Pathology

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Cerebral malaria is the most severe neurologic complication in children and young adults infected with Plasmodium falciparum. T-cell activation is required for development of Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (CM). To characterize the T-cell activation pathway involved, the role of protein kinase C-theta (PKC-) in experimental CM development was examined. PKC--deficient mice are resistant to CM development. In the absence of PKC-, no neurologic sign of CM developed after blood stage PbA infection. Resistance of PKC--deficient mice correlated with unaltered cerebral microcirculation and absence of ischemia, as documented by magnetic resonance imaging and magnetic resonance angiography, whereas wild-type mice developed distinct microvascular pathology. Recruitment and activation of CD8 ؉ T cells, and ICAM-1 and CD69 expression were reduced in the brain of resistant mice; however, the pulmonary inflammation and edema associated with PbA infection were still present in the absence of functional PKC-. Resistant PKC--deficient mice developed high parasitemia, and died at 3 weeks with severe anemia. Therefore, PKC-signaling is crucial for recruitment of CD8 ؉ T cells and development of brain microvascular pathology resulting in fatal experimental CM, and may represent a novel therapeutic target of CM.

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Section: Discussionmentioning

confidence: 99%

Protein Kinase C-Theta Is Required for Development of Experimental Cerebral Malaria

Fauconnier

Bourigault

Même

et al. 2011

The American Journal of Pathology

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“…Indeed, we have recently found, in muscle resistance arteries, that the fatty acid, palmitic acid, induces insulin-mediated vasoconstriction of muscle resistance arteries at concentrations observed in obesity, through the inhibition of the insulin-mediated activation of Akt and eNOS. PKCθ plays an important role in this interaction (Bakker et al 2008). This study suggests a direct interaction between free fatty acids (FFA) and insulin in the muscle microcirculation, leading to vasoconstriction of muscle resistance arteries.…”

Section: Adipokinesmentioning

confidence: 94%

“…However, the exact role of IRS in endothelial dysfunction in the microvasculature is not completely clear. PKCθ has recently been discovered in the vascular endothelium of mice and humans and is involved in disturbed insulinmediated vasoreactivity induced by fatty acids (Bakker et al 2008). PKCθ knock-out mice are protected from acute fatty-acid-induced insulin resistance , and an overactive PKCθ gene could be involved in endothelial dysfunction in type 2 diabetes.…”

Section: Genetic Predisposition For the Development Of Type 2 Diabetesmentioning

confidence: 99%

Endothelial dysfunction and diabetes: roles of hyperglycemia, impaired insulin signaling and obesity

et al. 2008

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Endothelial dysfunction comprises a number of functional alterations in the vascular endothelium that are associated with diabetes and cardiovascular disease, including changes in vasoregulation, enhanced generation of reactive oxygen intermediates, inflammatory activation, and altered barrier function. Hyperglycemia is a characteristic feature of type 1 and type 2 diabetes and plays a pivotal role in diabetesassociated microvascular complications. Although hyperglycemia also contributes to the occurrence and progression of macrovascular disease (the major cause of death in type 2 diabetes), other factors such as dyslipidemia, hyperinsulinemia, and adipose-tissue-derived factors play a more dominant role. A mutual interaction between these factors and endothelial dysfunction occurs during the progression of the disease. We pay special attention to the possible involvement of endoplasmic reticulum stress (ER stress) and the role of obesity and adipose-derived adipokines as contributors to endothelial dysfunction in type 2 diabetes. The close interaction of adipocytes of perivascular adipose tissue with arteries and arterioles facilitates the exposure of their endothelial cells to adipokines, particularly if inflammation activates the adipose tissue, and thus affects vasoregulation and capillary recruitment in skeletal muscle. Hence, an initial dysfunction of endothelial cells underlies metabolic and vascular alterations that contribute to the development of type 2 diabetes.

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“…14,15 This event has been used as a marker for activation of this PKC isoform in other cell system such as muscle resistance artery cells. 16 In platelets, PKC-has been reported to be tyrosine phosphorylated during outside-in and GPVI signaling at Tyr-90. 17 PKC-was found to contribute to receptor-mediated outside-in ␣ IIb ␤ 3 signaling and actin reorganization, but it was excluded to be a regulator in agonist-induced inside-out signaling and fibrinogen binding to ␣ IIb ␤ 3 .…”

Section: Introductionmentioning

confidence: 99%

Impaired activation of platelets lacking protein kinase C-θ isoform

Nagy

Bhavaraju

Getz

et al. 2009

Blood

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Protein kinase C (PKC) isoforms have been implicated in several platelet functional responses, but the contribution of individual isoforms has not been thoroughly evaluated. Novel PKC isoform PKC-is activated by glycoprotein VI (GPVI) and protease-activated receptor (PAR) agonists, but not by adenosine diphosphate. In human platelets, PKC--selective antagonistic (RACK; receptor for activated C kinase) peptide significantly inhibited GPVI and PARinduced aggregation, dense and ␣-granule secretion at low agonist concentrations. Consistently, in murine platelets lacking PKC-, platelet aggregation and secretion were also impaired. PKCmediated phosphorylation of tSNARE protein syntaxin-4 was strongly reduced in human platelets pretreated with PKC-RACK peptide, which may contribute to the lower levels of granule secretion when PKC-function is lost. IntroductionPlatelet activation plays an important role in hemostasis, and the abnormal activation of platelets leads to thrombosis. 1 After circulating platelets are exposed to collagen-rich subendothelium at the site of vascular injury, platelets become activated, release granule contents, and generate thrombin and the lipid mediator thromboxane A 2 (TXA 2 ). 2,3 Secreted adenosine diphosphate (ADP), serotonin, and TXA 2 amplify the initial stimulus in a positive feedback activation of platelets. 2,3 In addition, ␣-granule proteins, such as P-selectin, mediating adhesive interactions between platelets, leukocytes, and endothelial cells, play a pivotal role in the pathogenesis of thrombosis and inflammation. 4 Glycoprotein VI (GPVI) and G-protein-coupled protease-activated receptors (PARs) are 2 dominant signaling receptors that mediate many of the important functional responses in platelets. [1][2][3] There are significant similarities in GPVI and PAR signaling, as phospholipase C (PLC) is activated by both pathways, which results in the generation of inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3 mediates the release of Ca 2ϩ from intracellular stores, whereas DAG causes direct protein kinase C (PKC) activation. 3,5 Platelet aggregation requires the ␣ IIb ␤ 3 receptor to undergo a conformational change from a low-to a high-affinity state to bind ligands, such as fibrinogen, which is considered inside-out signaling. On the other hand, the pathway of outside-in signaling is induced by ligand binding to ␣ IIb ␤ 3 . 6,7 Human platelets express several PKC isoforms: ␣, ␤, , ⑀, ␦, , and . 8,9 Many functional responses, including platelet secretion, aggregation, and actin reorganization, have been shown to be positively regulated by PKC isoforms. 10 PKC-, as a member of PKC novel subfamily, is Ca 2ϩ -insensitive but This isoform contains a carboxyl-terminal catalytic domain with 2 conserved regions, C3 and C4, which are essential for catalytic activity and substrate binding, but lacks the calcium-binding C2 region. 12,13 After activation, PKC-is phosphorylated at threonine, serine (autophosphorylation site), and tyrosine residues. Among these, phosphorylation ...

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Protein Kinase C θ Activation Induces Insulin-Mediated Constriction of Muscle Resistance Arteries

Cited by 60 publications

References 52 publications

Protein Kinase C-Theta Is Required for Development of Experimental Cerebral Malaria

Protein Kinase C-Theta Is Required for Development of Experimental Cerebral Malaria

Endothelial dysfunction and diabetes: roles of hyperglycemia, impaired insulin signaling and obesity

Impaired activation of platelets lacking protein kinase C-θ isoform

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