Protein kinase C-α signals Rho-guanine nucleotide dissociation inhibitor phosphorylation and Rho activation and regulates the endothelial cell barrier function
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作者:
Mehta, D
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Univ Illinois, Coll Med, Dept Pharmacol, Chicago, IL 60612 USAUniv Illinois, Coll Med, Dept Pharmacol, Chicago, IL 60612 USA
Mehta, D
[1
]
Rahman, A
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Univ Illinois, Coll Med, Dept Pharmacol, Chicago, IL 60612 USAUniv Illinois, Coll Med, Dept Pharmacol, Chicago, IL 60612 USA
Rahman, A
[1
]
Malik, AB
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Univ Illinois, Coll Med, Dept Pharmacol, Chicago, IL 60612 USAUniv Illinois, Coll Med, Dept Pharmacol, Chicago, IL 60612 USA
Malik, AB
[1
]
机构:
[1] Univ Illinois, Coll Med, Dept Pharmacol, Chicago, IL 60612 USA
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 la-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-alpha. Moreover, the stimulation of human umbilical venular endothelial cells with thrombin induced rapid association of PKC-alpha with Rho, Activated PKC-alpha but not PKC-epsilon induced marked phosphorylation of GDI in vitro. Taken together, these results indicate that PKC-alpha is critical in regulating GDI phosphorylation, Rho activation, and in signaling Rho-dependent endothelial barrier dysfunction.
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INDIANA UNIV,SCH MED,RICHARD L ROUDEBUSH VET ADM MED CTR,DEPT MED,INDIANAPOLIS,IN 46202INDIANA UNIV,SCH MED,RICHARD L ROUDEBUSH VET ADM MED CTR,DEPT MED,INDIANAPOLIS,IN 46202
GARCIA, JGN
DAVIS, HW
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INDIANA UNIV,SCH MED,RICHARD L ROUDEBUSH VET ADM MED CTR,DEPT MED,INDIANAPOLIS,IN 46202INDIANA UNIV,SCH MED,RICHARD L ROUDEBUSH VET ADM MED CTR,DEPT MED,INDIANAPOLIS,IN 46202
DAVIS, HW
PATTERSON, CE
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INDIANA UNIV,SCH MED,RICHARD L ROUDEBUSH VET ADM MED CTR,DEPT MED,INDIANAPOLIS,IN 46202INDIANA UNIV,SCH MED,RICHARD L ROUDEBUSH VET ADM MED CTR,DEPT MED,INDIANAPOLIS,IN 46202
机构:
INDIANA UNIV,SCH MED,RICHARD L ROUDEBUSH VET ADM MED CTR,DEPT MED,INDIANAPOLIS,IN 46202INDIANA UNIV,SCH MED,RICHARD L ROUDEBUSH VET ADM MED CTR,DEPT MED,INDIANAPOLIS,IN 46202
GARCIA, JGN
DAVIS, HW
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h-index: 0
机构:
INDIANA UNIV,SCH MED,RICHARD L ROUDEBUSH VET ADM MED CTR,DEPT MED,INDIANAPOLIS,IN 46202INDIANA UNIV,SCH MED,RICHARD L ROUDEBUSH VET ADM MED CTR,DEPT MED,INDIANAPOLIS,IN 46202
DAVIS, HW
PATTERSON, CE
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h-index: 0
机构:
INDIANA UNIV,SCH MED,RICHARD L ROUDEBUSH VET ADM MED CTR,DEPT MED,INDIANAPOLIS,IN 46202INDIANA UNIV,SCH MED,RICHARD L ROUDEBUSH VET ADM MED CTR,DEPT MED,INDIANAPOLIS,IN 46202