p53 gene transfer to the injured rat carotid artery decreases neointimal formation

Scheinman, Marcel; Ascher, Enrico; Levi, Gabriel; Hingorani, Anil; Shirazian, Djamshid; Seth, Prem

doi:10.1016/s0741-5214(99)70389-7

Cited by 42 publications

(23 citation statements)

References 24 publications

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“…Adenoviruses were propagated in HEK 293 cells and purified by CsCl density gradient centrifugation. A recombinant adenovirus encoding for the wild-type p53 protein was a generous gift from Enrico Ascher (24,35).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

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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Section: Methodsmentioning

confidence: 99%

“…The importance of p53 is also confirmed in various animal models. Adenovirus-mediated gene transfer of p53 to rat carotid arteries inhibited neointimal formation following balloon injury (24), whereas target deletion of p53 led to larger intimal lesions in a mouse vein graft model (25).…”

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

confidence: 99%

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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“…Brachytherapy, based on the principle that proliferating cells are more sensitive to ionizing radiation, has shown favorable results in initial clinical trials, 2 but long-term efficacy and safety remain a concern. 3 In contrast, molecular approaches with transfer of the cytotoxic thymidine kinase, 4 retinoblastoma, 5 nitric oxide synthase (NOS), 6 -9 and tumor suppressor 10,11 genes have shown benefit in reducing neointima formation in rodent and porcine balloon-injured peripheral arteries. Most gene-based strategies have been tested in the carotid artery balloon denudation model.…”

mentioning

confidence: 99%

l -Arginine Administration Reduces Neointima Formation After Stent Injury in Rats by a Nitric Oxide-Mediated Mechanism

Vermeersch

Zhang

Stabile

et al. 2001

ATVB

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Abstract-The clinical outcome of vascular stenting is limited by in-stent stenosis. Increased nitric oxide (NO)/cGMP signaling by L-arginine (L-Arg) supplementation, the substrate for NO synthase (NOS), or NOS gene transfer may reduce in-stent neointima formation. After stenting, vascular cell proliferation in rat carotid arteries, as measured by 5Ј-bromodeoxyuridine (5Ј-BrdU) incorporation, indicated 15Ϯ8%, 28Ϯ5%, and 33Ϯ7% 5Ј-BrdU-positive vascular cells at 4, 7, and 14 days, respectively. Reporter ␤-galactosidase gene transfer efficacy was evidenced by 30% ␤-galactosidase-expressing medial smooth muscle cells at 14 days. The intima-to-media ratio (I/M) progressively increased to 2.32Ϯ0.24 at 14 days. To target in-stent neointima formation, animals were infected with adenoviral vectors (4ϫ10 10 plaque-forming units per mL) expressing NOS2 (AdNOS2) or no transgene (AdRR5), or they received daily doses of L-Arg (500 mg · kg Ϫ1 · dϪ1 IP). The neointima at 14 days was smaller in L-Arg-treated than in untreated rats (I/M 1.25Ϯ0.35 vs 2.32Ϯ0.24, PϽ0.05, nϭ7 each) or in AdRR5-and AdNOS2-infected rats (I/M 2.57Ϯ0.43, nϭ7 and 1.82Ϯ0.75, nϭ8, respectively; PϽ0.05 for both). The effect of L-Arg was abolished by simultaneous administration of N G -nitro L-arginine methyl ester, an NOS inhibitor (2.03Ϯ0.39, PϽ0.05, vs L-Arg). Inflammation was markedly less in L-Arg-and AdNOS2-treated than in AdRR5-infected rats. Supplemental L-Arg reduces neointima formation after stenting by way of an NOS-dependent mechanism and may be a valuable strategy to target in-stent stenosis. Key Words: arginine Ⅲ neointima formation Ⅲ gene therapy Ⅲ stents Ⅲ nitric oxide synthase T he most significant drawback of angioplasty and stenting remains in-stent stenosis with luminal narrowing, characterized by a fibroproliferative response and by increased matrix production. 1 Pharmacological interventions have proven ineffective in reducing in-stent stenosis in patients, spurring interest in alternative treatment strategies, including brachytherapy and intracoronary gene transfer. Brachytherapy, based on the principle that proliferating cells are more sensitive to ionizing radiation, has shown favorable results in initial clinical trials, 2 but long-term efficacy and safety remain a concern. 3 In contrast, molecular approaches with transfer of the cytotoxic thymidine kinase, 4 retinoblastoma, 5 nitric oxide synthase (NOS), 6 -9 and tumor suppressor 10,11 genes have shown benefit in reducing neointima formation in rodent and porcine balloon-injured peripheral arteries. Most gene-based strategies have been tested in the carotid artery balloon denudation model. However, in the majority of percutaneous interventions in patients, stent deployment is used, indicating the need for experimental stent-injury models to evaluate new therapies for restenosis.Strategies aimed at increasing local NO concentrations in the injured vessel wall by NOS transfer or by administration of L-arginine (L-Arg) reduced intimal hyperplasia in experimental balloon-injury models [1...

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“…23 In addition, it has been shown that wildtype p53 accumulates in human atherosclerotic tissues. 24 Moreover, adenovirus expression of p53 (Ad-p53) reduces cell proliferation in the rat carotid artery 25 or migration in the human saphenous vein 26 and conversely, antisense oligonucleotides to p53 increase proliferation. 27 All these studies suggest that p53 inhibits cell proliferation and promotes VSMC apoptosis in atherosclerosis, in vivo and in vitro.…”

Section: Discussionmentioning

confidence: 99%

p53 Levels Positively Correlate with Carotid Intima‐media Thickness in Patients with Subclinical Atherosclerosis

Chen

Wang

et al. 2009

Clinical Cardiology

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Background: The level of circulating p53 is related to inflammation in asymptomatic subjects with cardiovascular risk factors. Whether p53 is associated with the severity of atherosclerosis remains to be determined. Hypothesis: This study examines the relationship of systemic p53 levels with atherosclerotic risk factors and subclinical atherosclerosis. Methods: Circulating levels of p53 and markers of inflammation were measured in 356 subjects with cardiovascular risk factors but who were free from clinical cardiovascular disease. Subclinical atherosclerosis was evaluated by both the mean carotid intima-media thickness (IMT) and the presence of atherosclerotic plaques with the use of B-mode ultrasound in all subjects. Results: p53 levels were positively correlated with age (r = 0.382, P < 0.001), intercellular adhesion molecular-1 (ICAM-1; r = 0.510, P < 0.01), vascular cell adhesion molecular-1 (VCAM-1; r = 0.497, P < 0.01), E-selectin (r = 0.337, P < 0.01), and carotid IMT (r = 0.594, P < 0.01). The association between p53 and IMT remained significant in multiple regression analysis (P < 0.01) when controlling for traditional atherosclerotic risk factors and inflammatory markers. Conclusion: Higher plasma p53 levels were associated with an increase in inflammatory markers, as well as increased carotid IMT. Circulating p53 may be useful in identifying subclinical atherosclerosis in subjects symptomatically free from cardiovascular disease.

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p53 gene transfer to the injured rat carotid artery decreases neointimal formation

Abstract: Adenovirus-mediated gene transfer of p53 protein significantly decreases the formation of neointima in the rat carotid injury model. This may represent a potential therapy for restenosis in humans.

Cited by 42 publications

References 24 publications

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

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

l -Arginine Administration Reduces Neointima Formation After Stent Injury in Rats by a Nitric Oxide-Mediated Mechanism

p53 Levels Positively Correlate with Carotid Intima‐media Thickness in Patients with Subclinical Atherosclerosis

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