Protein kinase C β modulates thrombin-induced Ca2+ signaling and endothelial permeability increase

Vuong, Phuoc T.; Malik, Asrar B.; Nagpala, Pablito G.; Lum, Hazel

doi:10.1002/(sici)1097-4652(199806)175:3<379::aid-jcp16>3.0.co;2-0

Cited by 40 publications

(25 citation statements)

References 43 publications

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“…In contrast, ␣-thrombin stimulation of HMEC-AS enhanced the increase in endothelial permeability compared with HMEC-1 and HMEC-pLNCX (187). Thus PKC-␤1, via a negative feedback loop, modulates endothelial monolayer injury in response to ␣-thrombin (187). However, the role of PKC-␤1 changes with the mediator used to alter the endothelial function, because overexpression of the PKC-␤1 isotype augments the increase in endothelial permeability in response to PMA (as indicated above), as opposed to the suppressive role of PKC-␤1 during the response to ␣-thrombin (126).…”

Section: Pkc In Thrombin-induced Lung Endothelial Injurymentioning

confidence: 74%

“…␣-Thrombin induced a similar increase in permeability in HMEC-1 and HMEC-pLNCX. In contrast, ␣-thrombin stimulation of HMEC-AS enhanced the increase in endothelial permeability compared with HMEC-1 and HMEC-pLNCX (187). Thus PKC-␤1, via a negative feedback loop, modulates endothelial monolayer injury in response to ␣-thrombin (187).…”

Section: Pkc In Thrombin-induced Lung Endothelial Injurymentioning

confidence: 86%

“…PMA stimulated the translocation of PKC-␤1 from the cytosol to the membrane, indicating PKC-␤1 activation (126). In another study, a decrease in PKC-␤1 expression reduced the effect of PMA on barrier function (187). Interestingly, downregulation of PKC with PMA can delay the normalization of endothelial permeability that follows the altered barrier function in response to thrombin (see PKC IN THROMBIN-INDUCED LUNG ENDOTHE-LIAL INJURY), indicating that PKC isotypes have disparate roles in changing endothelial permeability that are dependent on the agonist used to induce the inflammatory response (105).…”

Section: Isotypes Of Pkc In Phorbol Ester-induced Lung Injurymentioning

confidence: 91%

“…Interestingly, a role for another PKC isotype is indicated in the response to ␣-thrombin in endothelial cells. In a human dermal microvascular endothelial cell line (HMEC-1), PKC-␤1 downregulates the ␣-thrombin receptor and suppresses the increase in endothelial permeability in response to ␣-thrombin (187). HMEC-1 transduced with full-length PKC-␤1 AS cDNA or control pLNCX vector created the stable cell lines HMEC-AS and HMEC-pLNCX, respectively.…”

Section: Pkc In Thrombin-induced Lung Endothelial Injurymentioning

confidence: 99%

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Protein kinase C modulates pulmonary endothelial permeability: a paradigm for acute lung injury

Siflinger-Birnboim

Johnson

2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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The intracellular serine/threonine kinase protein kinase C (PKC) has an important role in the genesis of pulmonary edema. This review discusses the PKC-mediated mechanisms that participate in the pulmonary endothelial response to agents involved in lung injury characteristic of the respiratory distress syndrome. Thus the paradigms of PKC-induced lung injury are discussed within the context of pulmonary transvascular fluid exchange. We focus on the signal transduction pathways that are modulated by PKC and their effect on lung endothelial permeability. Specifically, α-thrombin, tumor necrosis factor (TNF)-α, and reactive oxygen species are discussed because of their well-established roles in both human and experimental lung injury. We conclude that PKC, most likely PKC-α, is a primary supporter for lung endothelial injury in response to α-thrombin, TNF-α, and reactive oxygen species.

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Section: Pkc In Thrombin-induced Lung Endothelial Injurymentioning

confidence: 74%

Section: Pkc In Thrombin-induced Lung Endothelial Injurymentioning

confidence: 86%

Section: Isotypes Of Pkc In Phorbol Ester-induced Lung Injurymentioning

confidence: 91%

Section: Pkc In Thrombin-induced Lung Endothelial Injurymentioning

confidence: 99%

See 2 more Smart Citations

Protein kinase C modulates pulmonary endothelial permeability: a paradigm for acute lung injury

Siflinger-Birnboim

Johnson

2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…A PKC-dependent pathway is important in the mechanism of thrombin-induced increase in endothelial permeability (3,(27)(28)(29)(30). Because of the possibility that PKC may activate Rho by mediating Rho-GDI phosphorylation, we investigated the role of PKC in the mechanism of thrombin-induced Rho activation and in signaling the loss of endothelial barrier function in human umbilical venular endothelial (HUVE) cells.…”

mentioning

confidence: 99%

Protein Kinase C-α Signals Rho-Guanine Nucleotide Dissociation Inhibitor Phosphorylation and Rho Activation and Regulates the Endothelial Cell Barrier Function

Mehta

Rahman

Malik

2001

Journal of Biological Chemistry

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239

219

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The Rho-GDP guanine nucleotide dissociation inhibitor (GDI) complexes with the GDP-bound form of Rho and inhibits its activation. We investigated the role of protein kinase C (PKC) isozymes in the mechanism of Rho activation and in signaling the loss of endothelial barrier function. Thrombin and phorbol 12-myristate 13-acetate induced rapid phosphorylation of GDI and the activation of Rho-A in human umbilical venular endothelial cells. Inhibition of PKC by chelerythrine chloride abrogated the thrombin-induced GDI phosphorylation and Rho activation. Depletion of PKC prevented the thrombin-induced GDI phosphorylation and Rho activation, thereby indicating that these events occurred downstream of phorbol ester-sensitive PKC isozyme activation. The depletion of PKC or inhibition of Rho by C3 toxin also prevented the thrombin-induced decrease in transendothelial electrical resistance (a measure of increased transendothelial permeability), thus indicating that PKC-induced barrier dysfunction was mediated through Rho-dependent pathway. Using inhibitors and dominant-negative mutants, we found that Rho activation was regulated by PKC-␣. Moreover, the stimulation of human umbilical venular endothelial cells with thrombin induced rapid association of PKC-␣ with Rho. Activated PKC-␣ but not PKC-⑀ induced marked phosphorylation of GDI in vitro. Taken together, these results indicate that PKC-␣ is critical in regulating GDI phosphorylation, Rho activation, and in signaling Rhodependent endothelial barrier dysfunction.

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Depletion of protein kinase C? in normal and scleroderma lung fibroblasts has opposite effects on tenascin expression

Tourkina

Hoffman

Fenton

et al. 2001

Arthritis & Rheumatism

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Objective To determine whether the extracellular matrix protein tenascin‐C (TN‐C) is overexpressed in lung fibroblasts from systemic sclerosis (SSc) patients, the molecular mechanisms regulating TN‐C secretion in SSc and normal lung fibroblasts, and how these processes might contribute to lung fibrosis in SSc patients. Methods TN‐C secretion by SSc and normal fibroblasts was compared in vivo (in bronchoalveolar lavage [BAL] fluid) and in vitro (in culture medium). The ability of thrombin to induce TN‐C was confirmed at both the protein and the messenger RNA (mRNA) level. The role of protein kinase Cε (PKCε) in the expression of TN‐C was evaluated by determining the effects of thrombin on PKCε levels and by directly manipulating PKCε levels via the use of antisense oligonucleotides. Results BAL fluid from SSc patients contained high levels of TN‐C, whereas that from normal subjects contained little or no TN‐C. In vitro, SSc lung fibroblasts expressed much higher amounts of TN‐C than did normal lung fibroblasts. Consistent with the idea that thrombin is a physiologic inducer of TN‐C, thrombin stimulated TN‐C mRNA and protein expression in both SSc and normal lung fibroblasts by a mechanism that required proteolytic cleavage of the thrombin receptor. Surprisingly, thrombin treatment and antisense oligonucleotide–mediated depletion of PKCε indicated that TN‐C expression is regulated via opposite signaling mechanisms in SSc and normal cells. In SSc lung fibroblasts, thrombin decreased PKCε levels, and the decreased PKCε induced TN‐C secretion; in normal fibroblasts, thrombin increased PKCε levels, and the increased PKCε induced TN‐C secretion. Normal and SSc lung fibroblasts also differed in the subcellular localization of PKCε, both before and after thrombin treatment. Conclusion These studies are the first to demonstrate that thrombin is a potent simulator of TN‐C in lung fibroblasts and that PKCε is a critical regulator of TN‐C protein levels in these cells. Furthermore, our results indicate that both the regulation of PKCε levels by thrombin and the regulation of TN‐C levels by PKCε are defective in SSc lung fibroblasts.

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Protein kinase C β modulates thrombin-induced Ca2+ signaling and endothelial permeability increase

Cited by 40 publications

References 43 publications

Protein kinase C modulates pulmonary endothelial permeability: a paradigm for acute lung injury

Protein kinase C modulates pulmonary endothelial permeability: a paradigm for acute lung injury

Protein Kinase C-α Signals Rho-Guanine Nucleotide Dissociation Inhibitor Phosphorylation and Rho Activation and Regulates the Endothelial Cell Barrier Function

Depletion of protein kinase C? in normal and scleroderma lung fibroblasts has opposite effects on tenascin expression

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