Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The overgrowth of cells of the vessel wall, especially of the smooth muscle cells (SMCs), contributes to the pathogenesis of coronary atherosclerosis and wound repair after coronary angioplasty. However, the association between cellular proliferation in coronary lesions and clinical pathophysiology remains to be clarified in humans. Thus, we investigated proliferative activity in coronary tissues obtained from patients with coronary ischemia. The proliferative activity in tissues obtained by using directional coronary atherectomy (DCA) from 87 coronary lesions was assessed by immunohistochemical staining for the proliferating cell nuclear antigen (PCNA). The lesions were divided into 34 primary lesions and 53 postangioplasty lesions. The 34 primary tissue samples were obtained from 9 patients with stable angina pectoris (SAP) and 25 patients with acute coronary syndromes (ACS). Collectively, the 53 postangioplasty tissue samples were obtained from 37 patients with SAP and 16 patients with ACS. The PCNA labeling index (LI) was quantified as the mean percentage of PCNA-positive cells in the 3 most positive high-power fields (x 200). The mean LIs were high in the primary ACS samples [8.9 +/- 2.1% (p = 0.01)] and postangioplasty samples [2.3 +/- 0.8% (p = 0.08) in SAP cases and 4.1 +/- 2.4% (p = 0.06) in ACS cases] compared with the primary SAP samples (0.2 +/- 0.2%). Intimal hyperplasia, a random proliferation of SMCs (alpha-actin positive) was marked in the primary ACS samples (76%) as well as in the postangioplasty SAP (92%) and ACS (81%) samples, as compared with the primary SAP samples (33%) (p < 0.01). PCNA expression was mainly evident in the nucleus of the SMCs and CD68-positive macrophages. Many PCNA-positive cells were localized in plaque areas, as follows: intimal hyperplasia, neovascularized lesions, lesions with macrophage clusters, and lesions near areas of disrupted internal elastic lamina. The levels of PCNA expression in coronary lesions were not associated with the subsequent development of restenosis after DCA. Our findings suggest that the excessive proliferation of vascular wall cells, especially SMCs, is involved in the pathogenesis of ACS and in the process of wound repair after angioplasty in humans.
 ...
PMID:Comparison of proliferative activity in coronary plaques from patients with coronary ischemia. Histopathological and immunohistochemical analysis. 911 65

Experimental studies have implicated a functional role for the extracellular matrix glycoprotein thrombospondin-1 (TSP-1) in vascular smooth muscle cell proliferation and migration. We therefore sought to determine if TSP-1 might represent a specific component of the fibroproliferative tissue typically associated with restenosis lesions from human coronary and peripheral arteries. Positive immunostaining for TSP-1 was limited to hypocellular plaques typical of primary atherosclerosis; in contrast, such staining was nearly absent from the loose extracellular matrix of the fibroproliferative tissue typical of restenotic lesions. Only a small fraction of vascular smooth muscle cells in either primary or restenotic lesions demonstrated a cellular staining pattern for TSP-1, which was also observed in control studies performed in cell culture and in atherosclerotic rabbit arteries examined 3 days after experimental balloon angioplasty. Double-staining for TSP-1 and proliferating cell nuclear antigen in studies of human beings disclosed that only a small portion of proliferating cell nuclear antigen-positive cells also stained for TSP-1. The observations made in this series of specimens thus indicate that TSP-1 is not a major component of the extracellular matrix of human restenotic tissues, even when such specimens demonstrate evidence of hypercellularity or ongoing cellular proliferation. Because most restenosis specimens, however, were retrieved > or =1 month after the primary intervention, a functional role for TSP-1 in smooth muscle cell proliferation or migration at the early stages of lesion development is still possible.
 ...
PMID:Immunolocalization of thrombospondin-1 in human atherosclerotic and restenotic arteries. 948 88

Local accumulation of cells (hypercellularity) in the intima of the arterial wall as a result of cell proliferation is recognized as one of the major manifestations of human atherosclerosis. In the present study we have used a monoclonal antibody against PCNA to identify the proliferative activity, in uninvolved intima of human aorta classified as diffuse intimal thickening, and in different types of atherosclerotic lesions: specifically, initial lesion, fatty streak, fibroatheroma and fibrous plaque. As compared with a diffuse intimal thickening, the cell number in the initial lesions, fatty streaks and in a fibrolipid plaque (fibroatheroma) was 1.5-3-fold higher, while the cellularity in a fibrous plaque (fibrotic lesion) was lower than in a fibroatheroma and comparable with the cell number in the initial lesions. Using monoclonal antibodies, inflammatory cells (T- and B-lymphocytes as well as monocytes-macrophages) have been revealed in the intima. However, most (84-93%) of the intimal cells were noninflammatory cells classified as resident cells possessing the antigens of smooth muscle cells and pericytes as well as a small number of cells unidentifiable with the antibodies used. The highest number of proliferating cells was found in a fibroatheroma (11-fold higher as compared with a diffuse intimal thickening). A significant, but lesser increase of PCNA-positive cells was revealed in other types of lesions, too. The proliferative 'splash' in lipid-rich lesions suggests a relationship between the lipid accumulation in atherosclerotic intima and the stimulation of proliferation. The highest proliferative index of resident cells (i.e. percentage of the PCNA-positive cells among the total number of resident cells) was revealed in fibrotic lesions. It was approximately eight-fold higher than in a diffuse intimal thickening. The proliferative index of inflammatory cells considerably exceeded that of resident cells. However, in all types of atherosclerotic lesions and in a diffuse intimal thickening it showed no significant differences and was similar to the proliferative index of inflammatory cells isolated from peripheral blood. This suggests that an increased number of resident cells in atherosclerotic lesions can be explained by stimulation of their proliferative activity, whereas an altered inflammatory cell number is rather a result of their penetration from the blood into the subendothelial intima with a constant proliferative index.
Atherosclerosis 1998 Jul
PMID:Cell proliferation in normal and atherosclerotic human aorta: proliferative splash in lipid-rich lesions. 969 90

Sphingolipids and their metabolic products are now known to have second-messenger functions in a variety of cellular signaling pathways. Lactosylceramide (LacCer), a glycosphingolipid (GSL) present in vascular cells such as endothelial cells, smooth muscle cells, macrophages, neutrophils, platelets, and monocytes, contributes to atherosclerosis. Large amounts of LacCer accumulate in fatty streaks, intimal plaque, and calcified intimal plaque, along with oxidized low density lipoproteins (Ox-LDLs), growth factors, and proinflammatory cytokines. A possible role for LacCer in vascular cell biology was suggested when this GSL was found to stimulate the proliferation in vitro of aortic smooth muscle cells (ASMCs). A further link of LacCer in atherosclerosis was uncovered by the finding that Ox-LDLs stimulated specifically the biosynthesis of LacCer. Ox-LDL-stimulated endogenous synthesis of LacCer by activation of UDP-Gal:GlcCer,beta1-4galtransferase (GalT-2) is an early step in this signaling pathway. In turn, LacCer serves as a lipid second messenger that orchestrates a signal transduction pathway, ultimately leading to cell proliferation. This signaling pathway includes LacCer-mediated activation of NADPH oxidase that produces superoxide. Such superoxide molecules stimulate the GTP loading of p21(ras). Subsequently, the kinase cascade (Raf-1, Mek2, and p44MAPK [mitogen-activated protein kinase]) is activated. The phosphorylated form of p44MAPK translocates from the cytoplasm to the nucleus and engages in c-fos expression, proliferating cell nuclear antigen (PCNA) such as cyclin activation, and cell proliferation takes place. Interestingly, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), an inhibitor of GalT-2, can abrogate the Ox-LDL-mediated activation of GalT-2, the signal kinase cascade noted above, as well as cell proliferation. Additional studies have revealed that LacCer mediates the tumor necrosis factor-alpha (TNF-alpha)-induced nuclear factor-kappaB expression and intercellular adhesion molecule (ICAM-1) expression in vascular endothelial cells via the redox-dependent transcriptional pathway. LacCer also stimulates the expression of CD11/CD8, or Mac-1, on the surface of human neutrophils. Collectively, this phenomenon may contribute to the adhesion of neutrophils or monocytes to the endothelial cell surface and thus initiate the process of atherosclerosis. In addition, the LacCer-mediated proliferation of ASMCs may contribute to the progression of atherosclerosis. On the other hand, programmed cell death (apoptosis) by proinflammatory cytokines such as TNF-alpha, interleukin-1, and high concentrations of Ox-LDL occur via activation of a cell membrane-associated neutral sphingomyelinase (N-SMase). N-SMase hydrolyzes sphingomyelin into ceramide and phosphocholine. In turn, ceramide or a homologue serves as an important stress-signaling molecule. Interestingly, an antibody against N-SMase can abrogate Ox-LDL- and TNF-alpha-induced apoptosis and therefore may be useful for in vivo studies of apoptosis in experimental animals. Because plaque stability is an integral aspect of atherosclerosis management, activation of N-SMase and subsequent apoptosis may be vital events in the onset of plaque rupture, stroke, or heart failure. Interestingly, in human liver cells, N-SMase action mediates the TNF-alpha-induced maturation of the sterol regulatory-element binding protein. Moreover, a cell-permeable ceramide can reconstitute the phenomenon above in a sterol-independent fashion. Such findings may provide new avenues for therapy for patients with atherosclerosis. The findings described here indicate an important role for sphingolipids in vascular biology and provide an exciting opportunity for further research in vascular disease and atherosclerosis.
 ...
PMID:Sphingolipids in atherosclerosis and vascular biology. 976 22

The purpose of this study was to determine whether an angiotensin converting enzyme (ACE) inhibitor, benazepril, and an angiotensin receptor antagonist, valsartan, would decrease atherosclerotic severity in cholesterol-fed rabbits. Male rabbits were fed either: (a) normal rabbit chow; (b) 2% cholesterol diet; (c) 2% cholesterol diet supplemented by benazepril (3 mg/kg per day, subcutaneous injection); or (d) 2% cholesterol diet supplemented by valsartan (1 mg/kg per day, subcutaneous injection). After 12 weeks, the arteries were harvested for histomorphometry and immunohistochemistry. We observed that decreases in serum triglyceride (TG) and total cholesterol (TC) and ACE activity with benazepril-treatment were more than 60, 30, and 84%, respectively, in comparison with the cholesterol group; with valsartan-treatment, TG levels were 53% lower than in the cholesterol group, however, there was no significant difference in TC and ACE activity. The percentage of aortic surface atherosclerotic area, intimal thickness and the ratio of aortic intimal area to medial area were about 40% lower in the benazepril-treated group in comparison with those of the cholesterol group; the difference was more than 60% in the thoracic aorta. The valsartan-treated group had 23% less atherosclerotic area, less effective than benazepril treatment. The percent of PCNA-positive cells and the number of intimal proliferative cells/mm2 were significantly less in the benazepril-treated group compared with the cholesterol group (by 55 and 63%); these parameters were 35 and 17% lower, respectively, with valsartan. The ratio of proliferating macrophages to smooth muscle cells (SMCs) was 3:1 in the cholesterol group, 1:1 in the benazepril and 2:1 in the valsartan-treated group. These results indicate that benazepril could reduce atherosclerotic progression by decreasing macrophage proliferation and accumulation in the arterial wall. The mechanisms for reducing atherosclerotic progression by benazepril and valsartan may be related to reduction of TG and blockade of the angiotensin II action.
Atherosclerosis 1999 Apr
PMID:Antiatherogenic effect of angiotensin converting enzyme inhibitor (benazepril) and angiotensin II receptor antagonist (valsartan) in the cholesterol-fed rabbits. 1021 60

Intimal masses develop in the human coronary arteries of all humans, becoming atherosclerotic in later life either because of focal accumulation of lipid or the resulting response to injury. We evaluated the time course of formation of the intimal mass in the proximal left anterior descending coronary artery in autopsy specimens from 91 patients between 17 weeks' gestation and 23 months of postnatal age. Intima was rarely found before 30 weeks' gestation; however, the frequency with which at least some intimal cells were observed increased to 35% between 36 weeks' gestation and birth. By 3 months after birth, all patients had an intimal mass at this coronary location. The mean intima/media ratio was 0.1 just after birth and increased continuously to the second postnatal year. Replication of medial smooth muscle cells, indicated by proliferating cell nuclear antigen staining, was high before birth and decreased between birth and 2 years of age. However, the replication index of the intima remained at 2% to 5%. Thus, coronary intimal cells appearing in the perinatal period may arise by migration after replication of medial smooth muscle, as is seen in models of carotid artery balloon injury. In conclusion, formation of the coronary artery intima is a rapid process, beginning in the peripartum or postpartum period. Given the clonality of the adult lesion and the lack of proliferation in later stages of lesion formation, it is intriguing to speculate that this event may form the basis for atherosclerosis in later life.
 ...
PMID:Neonatal intima formation in the human coronary artery. 1047 43

There is a type of arteriosclerosis with remodeling of middle-size arteries in which intimal hyperplasia of smooth muscle cells (SMCs) plays the main role, and there are few macrophages, T lymphocytes, and foam cells. It is unknown whether apoptosis and the expression of Bax, an inducer of apoptosis, are increased according to the progression of this type of human arteriosclerosis, which is different from so-called atherosclerosis. Bax heterodimerizes with Bcl-2, an inhibitor of apoptosis, and the ratio of Bax to Bcl-2 determines cellular apoptosis or survival. Thus, we investigated apoptosis and the expressions of Bax, bax mRNA, and Bcl-2 in human arteriovenous (AV) fistulas used for hemodialysis, a representative of arteriosclerosis of the aforementioned type. The material was 20 radial arteries obtained from 20 patients with chronic renal failure undergoing AV shunt surgery. SMCs, macrophages, and T lymphocytes were immunohistochemically identified at the light microscopic (LM) level. Apoptosis was detected by in situ terminal deoxynucleotidyl transferase (TdT)-mediated digoxigenin-dUTP nick end labeling (TUNEL) at both the LM and electron microscopic (EM) level. Cell proliferating activity was estimated by proliferating cell nuclear antigen (PCNA). Bax and Bcl-2 were detected by immunohistochemistry and Western blot analysis. Expression of bax mRNA was detected by in situ hybridization. LM TUNEL-positive cells in both the intima and media were significantly increased according to the percent stenosis of the vessels. EM analysis revealed that ultrastructures of apoptotic SMCs were seen in both synthetic and contractile phenotypes. Their frequency of occurrence in the intima and media were greater in those vessels with >50% stenosis than in those with <50% stenosis (5.2+/-0.7% versus 1.0+/-0.3% in the intima and 2. 1+/-0.5% versus 0.2+/-0.1% in the media). The proportion of apoptotic SMCs with ruptured plasma membranes was greater than that of apoptotic SMCs with intact membranes in the intima of the former (4.1+/-0.6% versus 1.1+/-0.1%). Only those SMCs with apoptotic ultrastructures had TUNEL-positive nuclei with moderate or marked accumulation of immunogold particles at the EM level. However, ultrastructures of oncosis (primary necrosis) were not observed. Immunohistochemical analyses showed significant positive correlations between percent stenosis of vessels and the percentage of either PCNA-positive intimal cells or Bax-positive areas in the intima and media. Bcl-2-positive cells were not observed in the intima but mainly in the outer media. The percentage of Bcl-2-positive medial cells was definitely decreased at an early stage after formation of the AV fistula but did not change according to the duration of hemodialysis or the progression of arteriosclerosis. Western blot analysis of Bax or Bcl-2 and in situ hybridization of bax mRNA confirmed the immunohistochemical data. Thus, regulation of cellularity in intimal hyperplasia of SMCs in human arteriosclerosis with remodeling is mediated by proliferation and apoptosis but not oncosis. The apoptosis is probably induced by an increase in the Bax to Bcl-2 ratio.
 ...
PMID:Apoptosis and overexpression of bax protein and bax mRNA in smooth muscle cells within intimal hyperplasia of human radial arteries : analysis with arteriovenous fistulas used for hemodialysis. 1047 47

A hallmark of hyperlipidemia-induced atherosclerosis is altered gene expression that initiates cell proliferation and (de)differentiation in the intima of the arterial wall. The molecular signaling that mediates this process in vivo has yet to be identified. Extracellular signal-regulated kinases (ERKs) are thought to play a pivotal role in transmitting transmembrane signals required for cell proliferation in vitro. The present studies were designed to investigate the activity, abundance, and localization of ERK1/2 in atherosclerotic lesions of cholesterol-fed rabbits. Immunofluorescence analysis revealed abundant and heterogeneous distribution of ERK1/2, mainly localized in the cap and basal regions of atheromas. A population of ERK-enriched cells was identified as alpha-actin-positive smooth muscle cells (SMCs). ERK1 and 2 were heavily phosphorylated on tyrosyl residues and coexpressed with proliferating cell nuclear antigen in atherosclerotic lesions. ERK1/2 protein levels in protein extracts from atherosclerotic lesions were 2- to 3-fold higher than the vessels of chow-fed rabbits, and their activities were elevated 3- to 5-fold over those of the normal vessel. SMCs derived from atherosclerotic lesions had increased migratory/proliferative ability and higher ERK activity in response to LDL stimulation compared with cells from the normal vessel. Inhibition of ERK activation by PD98059, a specific inhibitor of mitogen-activated protein kinase kinases (MEK1/2), abrogated LDL-induced SMC proliferation in vitro. Taken together, our findings support the proposition that persistent activation and hyperexpression of ERK1/2 may be a critical element to initiate and perpetuate cell proliferation during the development of atherosclerosis.
 ...
PMID:Hyperexpression and activation of extracellular signal-regulated kinases (ERK1/2) in atherosclerotic lesions of cholesterol-fed rabbits. 1063 96

Arterial injury-induced vascular smooth muscle cell (VSMC) proliferation in intima is the important etiologic factor in vascular proliferative disorders such as atherosclerosis, hypertension and restenosis after balloon angioplasty. Butyrate, a naturally occurring short chain fatty acid, is produced by bacterial fermentation of dietary fiber and by mammary glands of certain mammals. Studies have shown that butyrate at millimolar concentrations, which are physiological, induces growth arrest, differentiation and apoptosis. We examined the effect of physiological concentrations of butyrate on rat VSMC proliferation and proliferation-induced PCNA expression to determine anti-atherogenic potential of butyrate. Butyrate concentrations, closer to physiological range, exhibited antiproliferative effects on both serum-induced proliferation of serum-starved quiescent VSMCs and actively proliferating non-confluent VSMCs. Treatment of serum-starved quiescent VSMCs with 1-8 mmol/l concentration of butyrate caused a concentration-dependent decrease in serum-induced VSMC proliferation and cell proliferation-associated increase in total cellular proteins and RNA levels. Similarly, exposure of actively growing VSMCs to 5 mmol/l butyrate resulted in the inhibition of cell proliferation and proliferation-induced increase in cellular proteins and RNA levels. Furthermore, cellular morphology was significantly altered. Analysis of cell cycle regulatory proteins indicated that levels of PCNA, an excellent marker for cell proliferation, was significantly altered by butyrate both in actively proliferating and serum-induced quiescent VSMCs. These observations suggest that butyrate exhibits potential antiatherogenic capability by inhibiting VSMC proliferation and proliferation-associated increase in PCNA expression and thus merits further investigations regarding therapeutic significance of butyrate in vascular proliferative disorders.
 ...
PMID:Butyrate inhibits proliferation-induced proliferating cell nuclear antigen expression (PCNA) in rat vascular smooth muscle cells. 1082 33

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


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>