Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To evaluate the effect of hypercholesterolemia on apoptosis and proliferation after vascular injury, iliac arteries of hypercholesterolemic (HC) and normocholesterolemic (NC) rabbits were examined after balloon injury using TUNEL, immunohistochemical staining of PCNA, macrophages, smooth muscle actin and p53. In media, apoptosis occurred massively early after injury and then decreased. HC did not affect this early post-injury apoptosis but significantly increased apoptosis 14 days later (D14). Immediate apoptosis in media was followed by active proliferation. HC sustained a high activity of proliferation until D14. The changes of immunoreactivity to p53 over the same 14 day period parallel that of apoptosis. In intima, where cells were scarce initially, proliferative activity reached a peak at D7 and then decreased. HC significantly enhanced proliferation at D14. In intima proliferation was accompanied by a later low-level apoptosis. HC significantly enhanced this low-level apoptosis at D14. These effects of HC resulted in significantly increased areas of intima and media. The fundamental difference between HC and NC was the infiltration of macrophages in HC. In conclusion, balloon injury induces early massive p53-associated apoptosis followed by proliferation in media, whereas in intima, it induces active proliferation followed by a low-level apoptosis. Hypercholesterolemia does not affect the early post-injury apoptosis but enhances proliferation and low-level apoptosis at a later stage, which in turn results in intimal and medial hyperplasia.
Atherosclerosis 2000 Jun
PMID:Effect of hypercholesterolemia on the sequential changes of apoptosis and proliferation after balloon injury to rabbit iliac artery. 1085 23

We investigated the influence of lovastatin, simvastatin and pravastatin on proliferation and viability of vascular smooth muscle cells (SMC) in vitro and studied the effects of lovastatin on a mouse SMC line transgenic for a temperature-sensitive mutant of SV40 large T antigen (TAg), known to inhibit the function of p53 and pRb family members. We found that lovastatin and simvastatin inhibited cell proliferation by provoking G0/G1 phase arrest with concomitant depression of the proliferation antigen Ki-67/MIB-1. Lovastatin at high concentrations of 20 micromol/l caused cell death in the presence of serum but not under serum starved conditions, which was verified on the basis of increased DNA strand breaks, decreased DNA content and morphological alterations seen by electron microscopy. Cell death was also found for simvastatin, whereas pravastatin did not exhibit antiproliferative or cytotoxic effects. Mouse SMC transgenic for TAg did not show any impaired sensitivity to the antiproliferative and cell death inducing effect of lovastatin, but both effects could be antagonized by the supplementation of mevalonate. The data indicate that antiproliferative and cytotoxic effects of lovastatin are caused by the using up of products of mevalonate metabolism and do not require the presence of p53 or pRb.
Atherosclerosis 2000 Jun
PMID:Differences in the effects of HMG-CoA reductase inhibitors on proliferation and viability of smooth muscle cells in culture. 1085 25

Apoptosis of arterial cells induced by oxidized low density lipoproteins (OxLDL) is thought to contribute to the progression of atherosclerosis. However, most data on apoptotic effects and mechanisms of OxLDL were obtained with extensively oxidized LDL unlikely to occur in early stages of atherosclerotic lesions. We now demonstrate that mildly oxidized LDL generated by incubation with oxygen radical-producing xanthine/xanthine oxidase (X/XO) induces apoptosis in primary cultures of human coronary endothelial and SMC, as determined by TUNEL technique, DNA laddering, and FACS analysis. Apoptosis was markedly reduced when X/XO-LDL was generated in the presence of different oxygen radical scavengers. Apoptotic signals were mediated by intramembrane domains of both Fas and tumor necrosis factor (TNF) receptors I and II. Blocking of Fas ligand (FasL) reduced apoptosis by 50% and simultaneous blocking of FasL and TNF receptors by 70%. Activation of apoptotic receptors was accompanied by an increase of proapoptotic and a decrease in antiapoptotic proteins of the Bcl-2 family and resulted in marked activation of class I and II caspases. Mildly oxidized LDL also activated MAP and Jun kinases and increased p53 and other transcription factors (ATF-2, ELK-1, CREB, AP-1). Inhibitors of Map and Jun kinase significantly reduced apoptosis. Our results provide the first evidence that OxLDL-induced apoptosis involves TNF receptors and Jun activation. More important, they demonstrate that even mildly oxidized LDL formed in atherosclerotic lesions may activate a broad cascade of oxygen radical-sensitive signaling pathways affecting apoptosis and other processes influencing the evolution of plaques. Thus, we suggest that extensive oxidative modifications of LDL are not necessary to influence signal transduction and transcription in vivo.
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PMID:Mildly oxidized low density lipoprotein activates multiple apoptotic signaling pathways in human coronary cells. 1102 84

Atherosclerosis is the most frequent cause of death in industrialized countries. Lesions are characterized by lipid deposits, focal thickening of the arterial wall with proliferation of smooth muscle cells (SMC), mononuclear infiltrates and neoformed vessels. In this paper, we studied the proliferative characteristics and cytogenetic alterations of SMC. These cells, expressing specific muscular actin, were diploid with an increased proliferative index for PCNA. A high percentage of SMC showed intense expression of p53. There were signs of chromosomal instability, being the most frequent findings chromosome 7 trisomy and chromosome 11 monosomy. Additionally, the gene for FGF-3 showed a marked amplification. These findings strongly suggest that SMC proliferation is active, and is related to the accumulation or mutation of the p53 oncoprotein. It also presents specific chromosomal alterations in close relation with growth factors. According to these findings SMC hyperplasia in the atherosclerosis plaque may be considered as a cellular clonal expansion.
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PMID:[Proliferative activity and chromosomal alterations of smooth muscle cells in atherosclerosis]. 1118 99

This study tested the hypothesis that c-Myc activation, an oxidation-sensitive transcription factor, and its binding partner Max occurs in coronary arteries of hypercholesterolemic (HC) pigs, and can be attenuated by chronic antioxidant intervention. Coronary arteries were isolated from normal, HC pigs, or HC supplemented with antioxidant vitamins (HC + vitamins). The expression of the c-Myc/Max complex, and its target genes GADD45 and p53, was studied in nonatherosclerotic, early lesions (LL), positively staining for oil-red-O, in adjacent lesion-prone regions (PL), and in healthy segments (HV). The expression of c-Myc and Max in HC was 2- to 3-fold greater in PL, and 4-fold in LL, compared to normal vessels (P < 0.01). The expression of GADD45 was down-regulated, and of p53 increased, in the same regions. These alterations were attenuated in the HC + vitamins. Thus, c-Myc activation is an early atherosclerosis, in both PL and LL coronary arterial regions, and can be blunted by chronic dietary antioxidant intervention.
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PMID:c-myc activation in early coronary lesions in experimental hypercholesterolemia. 1123 52

Apoptosis, a form of genetically programmed cell death, plays a key role in regulation of cellularity of the arterial wall. During atherogenesis, deregulated apoptosis may cause abnormalities of arterial morphogenesis, wall structural stability, and metabolisms. Many biophysiologic and biochemical factors, including mechanical forces, reactive oxygen and nitrogen species, cytokines, growth factors, oxidized lipoproteins, etc. may influence apoptosis of vascular cells. The Fas/Fas ligand/caspase death-signaling pathway, Bcl-2 protein family/mitochondria, the tumor suppressive gene p53, and the proto-oncogene c-myc may be activated in atherosclerotic lesions and mediate vascular apoptosis during the development of atherosclerosis. Abnormal expression and dysfunction of these apoptosis-regulating genes may attenuate or accelerate vascular cell apoptosis and affect the integrity and stability of plaques. Clarification of the molecular mechanism that regulates apoptosis may help design a new strategy for treatment of atherosclerosis and its major complication, the acute vascular syndromes.
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PMID:Biologic effect and molecular regulation of vascular apoptosis in atherosclerosis. 1128 45

Increased oxidative stress is a major characteristic of hypercholesterolemia-induced atherosclerosis. The oxidative environment is mainly created by the production of reactive oxygen species, which are assumed to mediate vascular tissue injury. Oxidative DNA damage resulting from free radical attack remains, however, a poorly examined field in atherosclerosis. Male New Zealand White rabbits were fed a cholesterol-rich diet (0.3%) for 24 weeks. The induced atherosclerotic plaques showed elevated levels of the DNA damage marker 7,8-dihydro-8-oxoguanine (8-oxoG) as demonstrated by immunohistochemistry. 8-oxoG immunoreactivity was found predominantly in the superficial layer of the plaque containing numerous macrophage-derived foam cells but not in the media or in arteries of age-matched control animals. Alkaline single-cell gel electrophoresis revealed that the number of DNA strand breaks was significantly higher in the plaque as compared with control samples of normolipemic animals. These changes were associated with the upregulation of DNA repair enzymes (poly[ADP-ribose] polymerase-1, p53, phospho-p53 [phosphorylated at Ser392], and XRCC1 [x-ray repair cross-complementing 1]). DNA strand breaks normalized after 4 weeks of dietary lipid lowering. However, a significant reduction of 8-oxoG immunoreactivity was only observed after a prolonged period of lipid lowering (12 to 24 weeks). Repair pathways started to decline progressively when cholesterol-fed animals were placed on a normal diet. In conclusion, oxidative DNA damage and increased levels of DNA repair, both associated with diet-induced hypercholesterolemia, are strongly reduced during dietary lipid lowering. These findings may provide a better insight into the benefits of lipid-lowering therapy on plaque stabilization.
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PMID:Oxidative DNA damage and repair in experimental atherosclerosis are reversed by dietary lipid lowering. 1130 84

Cell proliferation and cell death (either necrosis or apoptosis) are key processes in the progression of atherosclerosis. The tumor suppressor gene p53 is an essential gene in cell proliferation and cell death and is upregulated in human atherosclerotic plaques, both in smooth muscle cells and in macrophages. In the present study, we investigated the importance of macrophage p53 in the progression of atherosclerosis using bone marrow transplantation in APOE*3-Leiden transgenic mice, an animal model for human-like atherosclerosis. APOE*3-Leiden mice were lethally irradiated and reconstituted with bone marrow derived from either p53-deficient (p53(-/-)) or control (p53(+/+)) donor mice. Reconstitution of mice with p53(-/-) bone marrow did not result in any hemopoietic abnormalities as compared with p53(+/+) transplanted mice. After 12 weeks on an atherogenic diet, APOE*3-Leiden mice reconstituted with p53(-/-) bone marrow showed a significant (P=0.006) 2.3-fold increase in total atherosclerotic lesion area as compared with mice reconstituted with p53(+/+) bone marrow. Although likely a secondary effect of the increased lesion area, p53(-/-) transplanted mice also showed significantly more lesion necrosis (necrotic index, 1.1+/-1.3 versus 0.2+/-0.7; P=0.04) and lesion macrophages (macrophage area, 79.9+/-40.0 versus 39.7+/-27.3x10(3) micrometer(2) per section; P=0.02). These observations coincided with a tendency toward decreased apoptosis (terminal deoxynucleotidyl transferase end-labeling [TUNEL]-positive nuclei going from 0.42+/-0.39 to 0.14+/-0.15%, P=0.071), whereas the number of proliferating cells (5'-bromo-2'-deoxyuridine-positive nuclei) was not affected (3.75+/-0.98 versus 4.77+/-2.30%; P=0.59). These studies indicate that macrophage p53 is important in suppressing the progression of atherosclerosis and identify a novel therapeutic target for regulating plaque stability.
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PMID:Macrophage p53 deficiency leads to enhanced atherosclerosis in APOE*3-Leiden transgenic mice. 1132 63

Werner syndrome (WS) is an autosomal recessive disease manifested by the premature onset of age-related phenotypes, including diseases such as atherosclerosis and cancer. This mimicry of normal aging with the possible exception of central nervous system manifestations has made it a focus of recent molecular studies on the pathophysiology of aging. In culture, cells obtained from patients with WS are genetically unstable, characterized by an increased frequency of nonclonal translocations and extensive DNA deletions. The WS gene product (WRN) is a DNA helicase belonging to the RecQ family, but is unique within this family in that it also contains an exonuclease activity. In addition to unwinding double-stranded DNA, WRN helicase is able to resolve aberrant DNA structures such as G4 tetraplexes, triplexes and 4-way junctions. Concordant with this structure-specificity, WRN exonuclease preferentially hydrolyzes alternative DNA that contains bubbles, extra-helical loops, 3-way junctions or 4-way junctions. WRN has been shown to bind to and/or functionally interact with other proteins, including replication protein A (RPA), proliferating cell nuclear antigen (PCNA), DNA topoisomerase I, Ku 86/70, DNA polymerase delta and p53. Each of these interacting proteins is involved in DNA transactions including those that resolve alternative DNA structures or repair DNA damage. The biochemical activities of WRN and the functions of WRN associated proteins suggest that in vivo WRN resolves DNA topological or structural aberrations that either occur during DNA metabolic processes such as recombination, replication and repair, or are the outcome of DNA damage.
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PMID:Unwinding the molecular basis of the Werner syndrome. 1134 59

Patency of autologous human saphenous vein coronary artery bypass grafts (CABG) is compromised by intimal thickening and superimposed atherosclerosis, caused by migration of vascular smooth muscle cells (SMC) to the intima where they proliferate. Here, using adenoviral transfer, we have targeted SMCs using wild-type p53 (wt p53) overexpression. Initial in vitro analyses demonstrated that wt p53 overexpression had no effect on SMC proliferation but promoted apoptosis, which was inhibited by co-expression of bcl2 or crmA. Wt p53 inhibited SMC invasion through reconstituted matrices, a phenotype not affected by bcl2 or crmA. Overexpression of wt p53 in human saphenous vein before organ culture significantly induced apoptosis (P < 0.01, Student's t test) without affecting proliferation rates either in the media or in the intima. SMC migration was, however, significantly reduced by wt p53 (P < 0.01, Student's t test). Intimal thickening and the number of neointimal cells were reduced by 89% and 73%, respectively, after 14 days (P < 0.01 and P < 0.001, respectively, Student's t test). This study demonstrates that overexpression of wt p53 promotes apoptosis and inhibits migration of SMC leading to reduced intimal thickening. This maybe a useful approach for increasing patency rates in CABG procedures in the clinic.
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PMID:Wild-type p53 gene transfer inhibits neointima formation in human saphenous vein by modulation of smooth muscle cell migration and induction of apoptosis. 1140 61


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