Wild-type p53 gene transfer inhibits neointima formation in human saphenous vein by modulation of smooth muscle cell migration and induction of apoptosis

George, Sarah J.; Angelini, Gianni D; Capogrossi, Maurizio C.; Baker, Andrew H.

doi:10.1038/sj.gt.3301431

Cited by 76 publications

(70 citation statements)

References 31 publications

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“…28,35,36 In agreement with this, we found that serum deprivation of wild-type or mock-transfected VSMC-E1A cells resulted in rapid induction of p53 (Ϸ4-fold increase 1 hour after deprivation; Figure 6A). In contrast, the induction of p53 in mortalin-transfected cells was delayed for about 6 hours ( Figure 6A), suggesting that mortalin may inhibit apoptosis in VSMCs by reducing the level of p53.…”

Section: Mortalin Inhibits Apoptosis In Vsmcs Via the Inactivation Ofsupporting

confidence: 71%

Proteome Analysis and Functional Expression Identify Mortalin as an Antiapoptotic Gene Induced by Elevation of [Na ⁺ ] _i /[K ⁺ ] _i Ratio in Cultured Vascular Smooth Muscle Cells

Taurin

Seyrantepe

Orlov

et al. 2002

Circulation Research

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Abstract-Apoptosis of vascular smooth muscle cells (VSMCs) plays an important role in remodeling of vessel walls, one of the major determinants of long-term blood pressure elevation and an independent risk factor for cardiovascular morbidity and mortality. Recently, we have found that apoptosis in cultured VSMCs can be inhibited by inversion of the intracellular [Na ϩ ]/[K ϩ ] ratio after the sustained blockage of the Na ϩ ,K ϩ -ATPase by ouabain. To understand the mechanism of ouabain action, we analyzed subsets of hydrophilic and hydrophobic VSMC proteins from control and ouabain-treated cells by 2-dimensional electrophoresis. Ouabain treatment led to overexpression of numerous soluble and hydrophobic cellular proteins. Among proteins that showed the highest level of ouabain-induced expression, we identified mortalin (also known as GRP75 or PBP-74), a member of the heat shock protein 70 (HSP70) superfamily and a marker for cellular mortal and immortal phenotypes. Northern and Western blotting and immunocytochemistry all have confirmed that treatment of VSMCs with ouabain results in potent induction of mortalin expression. Transient transfection of cells with mortalin cDNA led to at least a 6-hour delay in the development of apoptosis after serum deprivation. The expression of tumor suppressor gene, p53, in mortalin-transfected cells was delayed to the same extent, and the expressed protein showed abnormal perinuclear distribution, suggesting that p53 is retained and inactivated by mortalin. Our studies therefore define a new [Na Key Words: apoptosis Ⅲ vascular smooth muscle Ⅲ proteome Ⅲ ion transport Ⅲ ouabain R emodeling of the blood vessel plays an important role in a variety of human vascular disorders, including hypertension, 1-3 atherosclerosis, 4 arterial injury, and restenosis after angioplasty. 5-7 Apoptosis (programmed cell death) of vascular smooth muscle cells (VSMCs) has recently been identified as the main factor contributing to the regulation of their number during remodeling, 8 -12 which inspired numerous studies of the mechanisms of the induction and progression of VSMC apoptosis. The execution phase of apoptosis in VSMCs is triggered similarly to that in the other cell types by activation of the caspase cascade, cleavage of intracellular proteins, and final disintegration of the cell. In contrast, the induction phase is specific for different subtypes of remodeling and involves the integration of multiple pro-and antiapoptotic signals, including the expression of death receptors, protooncogenes, and tumor suppressor genes. [13][14][15][16][17][18][19] Our recent studies showed that inhibition of the VSMC Na ϩ ,K ϩ pump with ouabain, or in K ϩ -free medium, rescues cells from apoptosis triggered by a number of factors including serum deprivation. 20 Equimolar substitution of extracellular Na ϩ with K ϩ completely abolished the effect of ouabain 20 showing that antiapoptotic action was indeed caused by the inversion of [NaThe development of cell death was blocked upstream of caspase-3 activati...

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Section: Mortalin Inhibits Apoptosis In Vsmcs Via the Inactivation Ofsupporting

confidence: 71%

Proteome Analysis and Functional Expression Identify Mortalin as an Antiapoptotic Gene Induced by Elevation of [Na ⁺ ] _i /[K ⁺ ] _i Ratio in Cultured Vascular Smooth Muscle Cells

Taurin

Seyrantepe

Orlov

et al. 2002

Circulation Research

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“…In particular, an important role of p53 in the pathogenesis of vascular diseases is suggested by decreased p53 levels in human restenotic (22) and atherosclerotic lesions (23). The importance of p53 is also confirmed in various animal models.…”

Section: Apoptosis Of Vascular Smooth Muscle Cells (Smcs)mentioning

confidence: 60%

Protein Kinase C Delta Induces Apoptosis of Vascular Smooth Muscle Cells through Induction of the Tumor Suppressor p53 by Both p38-dependent and p38-independent Mechanisms

Ryer

Sakakibara

Wang

et al. 2005

Journal of Biological Chemistry

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Apoptotic death of vascular smooth muscle cells (SMCs) is a prominent feature of blood vessel remodeling. In the present study, we examined the novel PKC isoform protein kinase C delta (PKC␦) and its role in vascular SMC apoptosis. In A10 SMCs, overexpression of PKC␦ was sufficient to induce apoptosis, whereas inhibition of PKC␦ diminished H 2 O 2 -induced apoptosis. Moreover, evidence is provided that the tumor suppressor p53 is an essential mediator of PKC␦-induced apoptosis in SMCs. Activation of PKC␦ led to accumulation as well as phosphorylation of p53 in SMCs; this induction correlated with apoptosis. Furthermore, blocking p53 induction with small interference RNA or targeted gene deletion prevented PKC␦-induced apoptosis, whereas restoring p53 expression rescued the ability of PKC␦ to induce apoptosis in p53 null SMCs. We also establish that PKC␦ regulates p53 at both transcriptional and post-translational levels. Specifically, the transcriptional regulation required p38 MAPK, whereas the post-translational modification, at least for serine 46, did not involve MAPK. Additionally, PKC␦, p38 MAPK, and p53 co-associate in cells under conditions favoring apoptosis. Together, our data suggest that SMC apoptosis proceeds through a pathway that involves PKC␦, the intermediary p38 MAPK, and the downstream target tumor suppressor p53. Apoptosis of vascular smooth muscle cells (SMCs)3 is a well established component of the remodeling that occurs during normal development of the circulatory system (1, 2) as well as during the course of neointimal formation after intervention for atherosclerosis (3-5). Because increased total cellularity is a prominent feature of an occluding neointima, the balance between proliferation and apoptosis during vessel healing appears central to this pathologic process (6, 7). Indeed, accumulating evidence suggests that abnormal SMC apoptosis leads to neointimal hyperplasia (8 -11). However, despite the importance of SMC apoptosis, the precise molecular mechanism underlying the regulation of apoptotic pathways in SMCs remains largely undetermined.Apoptosis is a multistage, genetically controlled process of selective cell deletion. Protein kinases regulate the early stages of apoptosis by phosphorylating key proteins (12, 13), whereas caspases, a family of cysteine proteases, are the main effectors whose activation results in the characteristic morphological changes associated with programmed cell death such as membrane blebbing, chromatin condensation, and DNA fragmentation (14,15).Members of the protein kinase C (PKC) family are activated by diverse stimuli and participate in multiple cellular processes such as growth, differentiation, and apoptosis (16). The novel PKC isoform, protein kinase C delta (PKC␦), has been shown to be associated with the response to DNA damage and other apoptotic stimuli in specific cell types (17)(18)(19)(20). The critical role of PKC␦ in vascular SMC apoptosis and pathogenesis of a neointimal lesion has been recently demonstrated using PKC␦ "knock-out" mice....

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“…In addition, several lines of evidence have suggested the functional linkage between TP53 and cell invasion and motility. For example, the overexpression of TP53 significantly reduced the invasion and migration of vascular smooth muscle cells (SMC) [5]. The deletion of TP53 led to actin cytoskeleton reorganization and a significant increase in cell motility in mouse embryonic fibroblast cells [6].…”

Section: Introductionmentioning

confidence: 99%

p53 dominant-negative mutant R273H promotes invasion and migration of human endometrial cancer HHUA cells

Dong

Tada

Hamada

et al. 2007

Clin Exp Metastasis

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Wild-type p53 gene transfer inhibits neointima formation in human saphenous vein by modulation of smooth muscle cell migration and induction of apoptosis

Cited by 76 publications

References 31 publications

Proteome Analysis and Functional Expression Identify Mortalin as an Antiapoptotic Gene Induced by Elevation of [Na ⁺ ] _i /[K ⁺ ] _i Ratio in Cultured Vascular Smooth Muscle Cells

Proteome Analysis and Functional Expression Identify Mortalin as an Antiapoptotic Gene Induced by Elevation of [Na ⁺ ] _i /[K ⁺ ] _i Ratio in Cultured Vascular Smooth Muscle Cells

Protein Kinase C Delta Induces Apoptosis of Vascular Smooth Muscle Cells through Induction of the Tumor Suppressor p53 by Both p38-dependent and p38-independent Mechanisms

p53 dominant-negative mutant R273H promotes invasion and migration of human endometrial cancer HHUA cells

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Wild-type p53 gene transfer inhibits neointima formation in human saphenous vein by modulation of smooth muscle cell migration and induction of apoptosis

Cited by 76 publications

References 31 publications

Proteome Analysis and Functional Expression Identify Mortalin as an Antiapoptotic Gene Induced by Elevation of [Na + ] i /[K + ] i Ratio in Cultured Vascular Smooth Muscle Cells

Proteome Analysis and Functional Expression Identify Mortalin as an Antiapoptotic Gene Induced by Elevation of [Na + ] i /[K + ] i Ratio in Cultured Vascular Smooth Muscle Cells

Protein Kinase C Delta Induces Apoptosis of Vascular Smooth Muscle Cells through Induction of the Tumor Suppressor p53 by Both p38-dependent and p38-independent Mechanisms

p53 dominant-negative mutant R273H promotes invasion and migration of human endometrial cancer HHUA cells

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Proteome Analysis and Functional Expression Identify Mortalin as an Antiapoptotic Gene Induced by Elevation of [Na ⁺ ] _i /[K ⁺ ] _i Ratio in Cultured Vascular Smooth Muscle Cells

Proteome Analysis and Functional Expression Identify Mortalin as an Antiapoptotic Gene Induced by Elevation of [Na ⁺ ] _i /[K ⁺ ] _i Ratio in Cultured Vascular Smooth Muscle Cells