Effects of Shear Stress on Protein Kinase C Distribution in Endothelial Cells

Hu, Ying-Li; Chien, Shu

doi:10.1177/002215549704500209

Cited by 27 publications

(21 citation statements)

References 40 publications

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“…There are numerous signaling cascades that are activated by FAs on the basal surface, leading to protein kinase C activation, tyrosine phosphorylation, and the phosphorylation of FA kinase (FAK) (34)(35)(36). Paxillin is a marker for FAK in the Src kinase pathway (37).…”

Section: Discussionmentioning

confidence: 99%

The role of the glycocalyx in reorganization of the actin cytoskeleton under fluid shear stress: A “bumper-car” model

Thi

Tarbell

Weinbaum

et al. 2004

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

289

308

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We propose a conceptual model for the cytoskeletal organization of endothelial cells (ECs) based on a major dichotomy in structure and function at basal and apical aspects of the cells. Intracellular distributions of filamentous actin (F-actin), vinculin, paxillin, ZO-1, and Cx43 were analyzed from confocal micrographs of rat fat-pad ECs after 5 h of shear stress. With intact glycocalyx, there was severe disruption of the dense peripheral actin bands (DPABs) and migration of vinculin to cell borders under a uniform shear stress (10.5 dyne͞cm 2 ; 1 dyne ‫؍‬ 10 N). This behavior was augmented in corner flow regions of the flow chamber where high shear stress gradients were present. In striking contrast, no such reorganization was observed if the glycocalyx was compromised. These results are explained in terms of a ''bumper-car'' model, in which the actin cortical web and DPAB are only loosely connected to basal attachment sites, allowing for two distinct cellular signaling pathways in response to fluid shear stress, one transmitted by glycocalyx core proteins as a torque that acts on the actin cortical web (ACW) and DPAB, and the other emanating from focal adhesions and stress fibers at the basal and apical membranes of the cell. mechanotransduction ͉ actin cortical web ͉ dense peripheral actin band H emodynamic shearing stresses on endothelial cells (ECs) are widely recognized as playing a vital role in the regulation of vessel wall remodeling, cellular signaling, mass transport, red and white cell interaction, and atherogenesis (1-3). The possible roles of the endothelial glycocalyx (EG) in this regulation as a molecular sieve, as a barrier and modulator of interactions between blood cells and ECs, and as a mechanotransducer of fluid shear stress have been studied more recently (4-7). Relatively little is known about the specific proteins in the EG, although hyaluronan, chondroitin, and heparan sulfate play a significant role in its assembly (8, 9). In the early 1990s, investigators first observed that the shear-induced dilation of small arteries was abolished when sialic acids were removed from the EG by neuraminidase (10). Florian et al. (11) recently verified the presence of heparan sulfate proteoglycan (HSPG) in the glycocalyx of cultured bovine aortic ECs and demonstrated that partial removal of HSPG with heparinase completely blocked shear-induced NO release. A puzzling and still not understood consequence of EG degradation was the observation that shear-induced NO production was greatly inhibited without apparent effect on shear-dependent vasodilation due to prostaglandin I 2 release (12). Squire et al. (13) showed that the ultrastructural organization of the EG was quasiperiodic, anchored to a geodesic-like scaffold of hexagonally arranged filamentous actin (F-actin) filaments forming an actin cortical web (ACW) (14) just beneath the plasmalemma. A fundamental question addressed in ref. 7 is how fluid shear stresses acting at the surface of the EG are transmitted to this ACW if there is essentially ...

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Section: Discussionmentioning

confidence: 99%

The role of the glycocalyx in reorganization of the actin cytoskeleton under fluid shear stress: A “bumper-car” model

Thi

Tarbell

Weinbaum

et al. 2004

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

289

308

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“…Vitamin E, if it did cause some or all of the switch in distribution, need not have done so by affecting NO; it has many actions. Its ability to inhibit the activation of protein kinase C (PKC) caused by lipoproteins 33 and other factors, 34 -36 an ability apparently unrelated to its antioxidant properties, 33,35,36 is of particular interest, since PKC is elevated in endothelial cells by shear stress 37,38 and has numerous effects in addition to its inhibitory influence on NO production. 39 The most convincing evidence for the proposed mechanism was that terminal plasma concentrations of nitrite and nitrate were higher in the trial II animals given vitamin E and cholesterol supplements than in the otherwise wellmatched group given cholesterol alone, correlating with the tendency to develop lesions with a more pronounced upstream distribution.…”

Section: Discussionmentioning

confidence: 99%

Two Patterns of Lipid Deposition in the Cholesterol-Fed Rabbit

Barnes¹,

Weinberg²

1999

ATVB

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Abstract-A central feature of arterial lipid deposition is its nonuniform and variable distribution. In immature human and rabbit aortas, spontaneous lesions occur most frequently downstream of branch points, but they tend to occur upstream of the same branches at later ages. In cholesterol-fed rabbits, the juvenile pattern has been seen regardless of age. These distributions may be determined by transport properties of the arterial wall, because uptake of plasma macromolecules is elevated downstream of aortic branches in immature rabbits and upstream in mature ones, except during cholesterol feeding, when the juvenile pattern is seen in adult vessels. The effect of cholesterol could reflect its inhibitory influence on the nitric oxide (NO) pathway because the adult transport pattern is NO dependent. Using protocols expected to preserve NO function and the mature pattern of transport during hypercholesterolemia, we made 2 attempts to induce upstream disease in rabbits. In trial I, plasma concentrations of cholesterol were kept within the normal human range for 15 weeks by using dietary levels of 0.05% to 0.2%. Although disease patterns reverse with age in human vessels exposed to these concentrations, lesions in both immature and mature rabbits occurred downstream of intercostal branch ostia. Trial II used older rabbits, a different base diet containing more vitamin E (96 mg/kg rather than 57 mg/kg), and higher levels of cholesterol (1%, administered for 8 weeks). For some animals, extra vitamin E (2000 mg/kg) was added to the diet. The mature pattern of lipid deposition was apparent around intercostal branches in the first group and was accentuated by the additional vitamin E, a change that was associated with a significant increase in the plasma concentration of NO metabolites. Spontaneous lesions, assessed on the base diet, were too rare to have influenced these distributions. This is the first report of upstream disease in the cholesterol-fed rabbit. The results support but do not prove the view that NO and transport are important in atherogenesis. (Arterioscler Thromb Vasc Biol.

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“…Cyclic strain to ECs results in a biphasic increase in DAG (17) that corresponds to early transient PKC activity followed by sustained elevated PKC activity (33). Although PKC involvement in mechanical force-induced endothelial responses has been acknowledged (33), studies have indicated only that specific isoforms PKC-⑀ and PKC-␤ are involved in shear-induced endothelial response (21,34). The mechanisms as to what and how PKC isoforms are involved in cellular responses to mechanical forces remain unclear.…”

Section: Sequential Activation Of Pkc-␣ and -⑀ Contributes To Strainimentioning

confidence: 99%

Sequential Activation of Protein Kinase C (PKC)-α and PKC-ε Contributes to Sustained Raf/ERK1/2 Activation in Endothelial Cells under Mechanical Strain

Cheng

Wung

Chao

et al. 2001

Journal of Biological Chemistry

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Endothelial cells (ECs) are constantly subjected to hemodynamic forces including cyclic pressure-induced strain. The role of protein kinase C (PKC) in cyclic strain-treated ECs was studied. PKC activities were induced as cyclic strain was initiated. Cyclic strain to ECs caused activation of PKC-␣ and -⑀. The translocation of PKC-␣ and -⑀ but not PKC-␤ from the cytosolic to membrane fraction was observed. An early transient activation of PKC-␣ versus a late but sustained activation of PKC-⑀ was shown after the onset of cyclic strain. Consistently, a sequential association of PKC-␣ and -⑀ with the signaling molecule Raf-1 was shown. ECs treated with a PKC inhibitor (calphostin C) abolished the cyclic strain-induced Raf-1 activation. ECs under cyclic strain induced a sustained activation of extracellular signalregulated protein kinases (ERK1/2), which was inhibited by treating ECs with calphostin C. ECs treated with a specific Ca 2؉ -dependent PKC inhibitor (Go 6976) showed an inhibition in the early phase of ERK1/2 activation but not in the late and sustained phase. ECs transfected with the antisense to PKC-␣, the antisense to PKC-⑀, or the inhibition peptide to PKC-⑀ reduced strain-induced ERK1/2 phosphorylation in a temporal manner. PKC-␣ mediated mainly the early ERK1/2 activation, whereas PKC-⑀ was involved in the sustained ERK1/2 activation. Strained ECs increased transcriptional activity of Elk1 (an ERK1/2 substrate). ECs transfected with the antisense to each PKC isoform reduced Elk1 and monocyte chemotactic protein-1 promotor activity. Our findings conclude that a sequential activation of PKC isoform (␣ and ⑀) contribute to Raf/ERK1/2 activation, and PKC-⑀ appears to play a key role in endothelial adaptation to hemodynamic environment.

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Effects of Shear Stress on Protein Kinase C Distribution in Endothelial Cells

Cited by 27 publications

References 40 publications

The role of the glycocalyx in reorganization of the actin cytoskeleton under fluid shear stress: A “bumper-car” model

The role of the glycocalyx in reorganization of the actin cytoskeleton under fluid shear stress: A “bumper-car” model

Two Patterns of Lipid Deposition in the Cholesterol-Fed Rabbit

Sequential Activation of Protein Kinase C (PKC)-α and PKC-ε Contributes to Sustained Raf/ERK1/2 Activation in Endothelial Cells under Mechanical Strain

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