Dataset Information

Protein kinase C delta mediates arterial injury responses through regulation of vascular smooth muscle cell apoptosis.

ABSTRACT:

Aims

A balance between apoptosis and proliferation of vascular smooth muscle cells (VSMC) influences the development of intimal hyperplasia. We have previously demonstrated that protein kinase C delta (PKCdelta) regulates both apoptosis and proliferation of VSMC in vitro. Here we investigate the role of PKCdelta in intimal hyperplasia through gene deletion or overexpression in rodent models of arterial injury.

Methods and results

Arterial injury was induced in mice and rats by means of carotid ligation or balloon angioplasty, respectively. Overexpression of PKCdelta was achieved by adenovirus-mediated gene transfer immediately after balloon injury in rat carotid arteries. Levels of PKCdelta protein were profoundly increased in the carotid wall 3-7 days after balloon injury, co-localizing to TUNEL-positive medial cells. When subjected to arterial injury, PKCdelta gene-deficient mice responded with an enhanced intimal hyperplasia accompanied by an 80% reduction in the number of TUNEL-positive cells detected in the injured arteries as compared with their wild-type littermates. Conversely, arterial gene transfer of PKCdelta further increased the arterial expression of PKCdelta, which was associated with a marked increase in apoptosis and reduction of intimal hyperplasia. Neither manipulation led to significant alteration in cell proliferation, suggesting that the function of PKCdelta after arterial injury is predominantly pro-apoptotic. This notion is further supported by our observation of high PKCdelta expression in human restenotic lesions that also co-localized with apoptosis.

Conclusion

The expression of PKCdelta is upregulated in the arterial wall in response to injury. This induction appears to be a mechanism of arterial response that negatively influences the degree of intimal hyperplasia by stimulating VSMC apoptosis.

SUBMITTER: Yamanouchi D

PROVIDER: S-EPMC2860709 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Publications

Protein kinase C delta mediates arterial injury responses through regulation of vascular smooth muscle cell apoptosis.

Yamanouchi Dai D Kato Kaori K Ryer Evan J EJ Zhang Fan F Liu Bo B

Cardiovascular research 20091006 3

<h4>Aims</h4>A balance between apoptosis and proliferation of vascular smooth muscle cells (VSMC) influences the development of intimal hyperplasia. We have previously demonstrated that protein kinase C delta (PKCdelta) regulates both apoptosis and proliferation of VSMC in vitro. Here we investigate the role of PKCdelta in intimal hyperplasia through gene deletion or overexpression in rodent models of arterial injury.<h4>Methods and results</h4>Arterial injury was induced in mice and rats by mea ...[more]

PMID: 19808702

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Project description:BackgroundAmong older adults, arterial aging is the major factor contributing to increased risk for cardiovascular disease-related morbidity and mortality. The chronic vascular inflammation that accompanies aging causes diffuse intimal-medial thickening of the arterial wall, thus increasing the vulnerability of aged vessels to vascular insults. Milk fat globule-epidermal growth factor 8 (MFG-E8) is a biomarker for aging arteries. This integrin-binding glycoprotein, induced by angiotensin II, facilitates vascular smooth muscle cell (VSMC) proliferation and invasion in aging vasculatures. This study investigated whether MFG-E8 directly mediates the initial inflammatory responses in aged arteries or VSMCs.MethodsA model of neointimal hyperplasia was induced in the common carotid artery (CCA) of aged mice to exacerbate age-associated vascular remodeling. Recombinant MFG-E8 (rMFG-E8) was administered to the injured artery using Pluronic gel to accentuate the effect on age-related vascular pathophysiology. The MFG-E8 level, leukocyte infiltration, and proinflammatory cell adhesion molecule (CAM) expression in the arterial wall were evaluated through immunohistochemistry. By using immunofluorescence and immunoblotting, the activation of the critical proinflammatory transcription factor nuclear factor (NF)-κB in the injured CCAs was analyzed. Immunofluorescence, immunoblotting, and quantitative real-time polymerase chain reaction were conducted using VSMCs isolated from the aortas of young and aged mice to assess NF-κB nuclear translocation, NF-κB-dependent gene expression, and cell proliferation. The extent of intimal-medial thickening in the injured vessels was analyzed morphometrically. Finally, Transwell migration assay was used to examine VSMC migration.ResultsEndogenous MFG-E8 expression in aged CCAs was significantly induced by ligation injury. Aged CCAs treated with rMFG-E8 exhibited increased leukocyte extravasation, CAM expression, and considerably increased NF-κB activation induced by rMFG-E8 in the ligated vessels. Exposure of early passage VSMCs from aged aortas to rMFG-E8 substantially increased NF-κB activation, proinflammatory gene expression, and cell proliferation. However, rMFG-E8 attenuated VSMC migration.ConclusionsMFG-E8 promoted the proinflammatory phenotypic shift of aged VSMCs and arteries, rendering the vasculature prone to vascular diseases. MFG-E8 may constitute a novel therapeutic target for retarding the aging processes in such vessels.

Dataset Information

Protein kinase C delta mediates arterial injury responses through regulation of vascular smooth muscle cell apoptosis.

Aims

Methods and results

Conclusion

Publications

Protein kinase C delta mediates arterial injury responses through regulation of vascular smooth muscle cell apoptosis.

Similar Datasets

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