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- W2107533958 abstract "Introduction: Transforming growth factor–beta (TGFβ), a cytokine implicated in the formation of intimal hyperplasia, potently inhibits the proliferation of vascular smooth muscle cells (SMCs). We have previously shown that TGF® inhibits proliferation by suppressing the expression of cyclin A, a cell cycle regulatory protein required for the G1-S phase transition. The purpose of the current study is to determine whether the novel protein kinase C, PKCδ, is an additional signaling intermediate in the pathway through which TGF® inhibits SMC proliferation. Methods: Rat SMCs (A10) were infected with an adenoviral vector expressing PKC™ (AdPKC™), a kinase dead mutant (Ad™KD), or empty viral vector (AdNull) and treated with TGFβ1 (5 ng/ml). Protein levels from cell lysates were analyzed by Western blot analysis. Results: We began our studies by evaluating whether TGF® activates PKC™. Following 30 min of TGFβ1 treatment, we observed a 66.3±7.6% (p<0.05) increase in PKC™ activity, as measured by a decrease in cytosolic and an increase membrane-associated PKC™. Next, we evaluated PKC™’s effect on the expression of cyclin A. Ectopic expression of PKCδ, via adenoviral transfection, decreased cyclin A protein levels in both control and TGFβ-treated cells. Conversely, inhibition of PKCδ, via a kinase dead mutant (AdδKD), blocked TGF®’s ability to downregulate cyclin A (Figure A). To investigate the mechanism by which PKCδ modulates cyclin A expression, we examined whether PKCδ activation influenced the phosphorylation of the cAMP responsive element binding protein (CREB), a critical step in the regulation of cyclin A. Ectopic expression of PKCδ induced CREB phosphorylation by 32.7% (p<0.05). Moreover, compared to the empty viral vector (AdNull), inhibition of PKCδ with AdδKD attenuated TGF®1-stimulated CREB phosphorylation (Figure B). Conclusion: We demonstrate here that PKCδ is necessary for TGF®1’s downregulation of cyclin A gene expression and inhibition of vascular SMC proliferation through the induction of CREB phosphorylation. The above experiments suggest the following temporal signaling sequence: TGF®→PKCδ→phospho-CREB→↓cyclin A→↓ SMC proliferation. PKCδ may serve as a novel gene target in therapies designed to inhibit SMC proliferation and prevent the development of intimal hyperplasia." @default.
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- W2107533958 date "2006-02-01" @default.
- W2107533958 modified "2023-09-26" @default.
- W2107533958 title "Transforming growth factor—beta inhibits vascular smooth muscle cell proliferation through a mechanism that involves protein kinase C-delta and cyclin a" @default.
- W2107533958 doi "https://doi.org/10.1016/j.jss.2005.11.009" @default.
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