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Protein kinase C ? regulates the release of collagen type I from vascular smooth muscle cells via regulation of Cdc42.

ABSTRACT: Collagen type I is the most abundant component of extracellular matrix in the arterial wall. Mice knocked out for the protein kinase C ? gene (PKC? KO) show a marked reduction of collagen I in the arterial wall. The lack of PKC? diminished the ability of arterial smooth muscle cells (SMCs) to secrete collagen I without significantly altering the intracellular collagen content. Moreover, the unsecreted collagen I molecules accumulate in large perinuclear puncta. These perinuclear structures colocalize with the trans-Golgi network (TGN) marker TGN38 and to a lesser degree with cis-Golgi marker (GM130) but not with early endosomal marker (EEA1). Associated with diminished collagen I secretion, PKC? KO SMCs exhibit a significant reduction in levels of cell division cycle 42 (Cdc42) protein and mRNA. Restoring PKC? expression partially rescues Cdc42 expression and collagen I secretion in PKC? KO SMCs. Inhibition of Cdc42 expression or activity with small interfering RNA or secramine A in PKC? WT SMCs eliminates collagen I secretion. Conversely, restoring Cdc42 expression in PKC? KO SMCs enables collagen I secretion. Taken together, our data demonstrate that PKC? mediates collagen I secretion from SMCs, likely through a Cdc42-dependent mechanism.

SUBMITTER: Lengfeld J

PROVIDER: S-EPMC3350558 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Protein kinase C δ regulates the release of collagen type I from vascular smooth muscle cells via regulation of Cdc42.

Lengfeld Justin J Wang Qiwei Q Zohlman Andrew A Salvarezza Susana S Morgan Stephanie S Ren Jun J Kato Kaori K Rodriguez-Boulan Enrique E Liu Bo B

Molecular biology of the cell 20120328 10

Collagen type I is the most abundant component of extracellular matrix in the arterial wall. Mice knocked out for the protein kinase C δ gene (PKCδ KO) show a marked reduction of collagen I in the arterial wall. The lack of PKCδ diminished the ability of arterial smooth muscle cells (SMCs) to secrete collagen I without significantly altering the intracellular collagen content. Moreover, the unsecreted collagen I molecules accumulate in large perinuclear puncta. These perinuclear structures coloc ...[more]

PMID: 22456512

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Project description:ObjectiveWe examined the role of syndecan-1 in modulating the phenotype of vascular smooth muscle cells in the context of endogenous inflammatory factors and altered microenvironments that occur in disease or injury-induced vascular remodeling.Methods and resultsVascular smooth muscle cells (vSMCs) display a continuum of phenotypes that can be altered during vascular remodeling. While the syndecans have emerged as powerful and complex regulators of cell function, their role in controlling vSMC phenotype is unknown. Here, we isolated vSMCs from wild type (WT) and syndecan-1 knockout (S1KO) mice. Gene expression and western blotting studies indicated decreased levels of α-smooth muscle actin (α-SMA), calponin, and other vSMC-specific differentiation markers in S1KO relative to WT cells. The spread area of the S1KO cells was found to be greater than WT cells, with a corresponding increase in focal adhesion formation, Src phosphorylation, and alterations in actin cytoskeletal arrangement. In addition, S1KO led to increased S6RP phosphorylation and decreased AKT and PKC-α phosphorylation. To examine whether these changes were present in vivo, isolated aortae from aged WT and S1KO mice were stained for calponin. Consistent with our in-vitro findings, the WT mice aortae stained higher for calponin relative to S1KO. When exposed to the inflammatory cytokine TNF-α, WT vSMCs had an 80% reduction in syndecan-1 expression. Further, with TNF-α, S1KO vSMCs produced increased pro-inflammatory cytokines relative to WT. Finally, inhibition of interactions between syndecan-1 and integrins αvβ3 and αvβ5 using the inhibitory peptide synstatin appeared to have similar effects on vSMCs as knocking out syndecan-1, with decreased expression of vSMC differentiation markers and increased expression of inflammatory cytokines, receptors, and osteopontin.ConclusionsTaken together, our results support that syndecan-1 promotes vSMC differentiation and quiescence. Thus, the presence of syndecan-1 would have a protective effect against vSMC dedifferentiation and this activity is linked to interactions with integrins αvβ3 and αvβ5.

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Protein kinase C ? regulates the release of collagen type I from vascular smooth muscle cells via regulation of Cdc42.

Publications

Protein kinase C δ regulates the release of collagen type I from vascular smooth muscle cells via regulation of Cdc42.

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