摘要:

Activation of the gene for inducible cyclooxygenase (cyclooxygenase-2 [Cox-2], prostaglandin endoperoxide synthase) is an early response to injury in vascular smooth muscle cells. We used in vitro and in vivo models to demonstrate that activation of quiescent smooth muscle cells by mitogens leads to a rapid, short-term rise in mRNA for Cox-2, followed by synthesis of new Cox-2 enzyme protein and a marked increase in prostaglandin production that depends on new enzyme synthesis. Moreover, the Cox-2 mRNA response observed in smooth muscle cells differs in both time and degree, depending on the particular mitogenic stimulus. Serum, platelet-derived growth factor, epidermal growth factor, and thrombin are strong inducers of Cox-2 mRNA, whereas acidic and basic fibroblast growth factors and interleukin-la are weak inducers. In contrast to the transient activation of Cox-2 in vitro after introduction of a mitogenic stimulus, the Cox-2 response after in vivo vascular injury extends over many days and may represent protracted cellular activation. During induction of Cox-2 message and protein, expression of constitutive cyclooxygenase (Cox-1) remains unchanged, however. These data suggest a pathophysiological role for Cox-2 in the early modulation of vascular responses to injury.

ISSN:1049-8834    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

An increase in dermatan sulfate-proteoglycan (DSPG) production occurs in cultured aortic smooth muscle cells exposed to macrophage-conditioned media, an effect that is abrogated by an antibody to interleukin-1 (IL-1). To determine which DSPG gene was regulated, cultured arterial smooth muscle cells from monkeys (Macaca fascicularis) were treated with 0 to 500 pg/mL human recombinant IL-la or IL-1/3 in the presence of [35S]sulfate and [3H]serine. Proteoglycans were isolated from the culture media and purified by selective precipitation and chromatography. Both recombinant IL-la and IL-10 caused a dose-response increase in DSPG production. Northern blot analysis of mRNA isolated from the cells identified 1.6-kb and 2.6-kb transcripts homologous to the cDNA encoding human decorin and biglycan, respectively. IL-1 treatment resulted in increases in the steady-state level of decorin mRNA as high as fourfold to sixfold at 500 pg/mL recombinant 1L-/3. By contrast, mRNA for biglycan was unchanged. Western blotting confirmed a specific enhancement of the 45-kD decorin core protein. These data indicate that IL-1 has differential effects on the two DSPG genes and suggest that macrophages may be capable of modifying the extracellular matrix of the artery wall by enhancing smooth muscle cell decorin production.

ISSN:1049-8834    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Among other Chinese herb drugs,Panax notoginsengis used to treat cardiovascular diseases. To elucidate any possible effects of this drug on the hemostatic system in vitro, we analyzed the influence of one of its major active constituents on fibrinolytic parameters of cultured human umbilical vein endothelial cells (HUVECs). When confluent cultures of HUVECs (passages 2 to 3) were conditioned with purified notoginsenoside Rl (NR1), a dose (0.01 to 100figNRl/mL) and time-dependent increase in tissue-type plasminogen activator (TPA) synthesis was observed, which was significant from 0.1 jig NRl/mL and from 6 hours of incubation with 100/xg NRl/mL on. TPA antigen increased from 3.9 ±0.2 ng per 1% cells per 24 hours to 8.0±0.5 ng per 105cells per 24 hours on addition of 100/ig NRl/mL. In contrast, no change in urokinase-type plasminogen activator and plasminogen activator inhibitor-1 (PAI-1) antigen synthesis was seen. There was also no effect of NR1 on PAI-1 deposition in the extracellular matrix. As judged from fibrin autography and reverse fibrin autography, TPA activity and TPA-PAI-1 complexes reached a maximal stimulation of more than threefold and twofold, respectively, at a concentration of 100figNRl/mL in conditioned media. On the contrary, NR1 induced a more than fivefold decrease in PAI-1 activity at the same concentration of NR1 in conditioned media. On Northern blot analysis of RNA obtained from NRl-stimulated and control HUVECs, NR1 induced a significant increase in TPA mRNA (192% of control value at 100/xg NRl/mL) while PAI-1 mRNA remained unchanged. Our data indicate that in fact NR1 contained in the Chinese herb used to treat cardiovascular diseases can induce a profibrinolytic response in cultured HUVECs, an effect that may also be operative in vivo.

ISSN:1049-8834    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The proliferation of vascular smooth muscle cells (SMCs) is a key event in the development of atherosclerotic lesions and in the restenosis of arteries after angioplasty. Porypeptide growth factors are potent SMC mitogens in vitro and are believed to be involved in SMC proliferation in vivo. Strong data exist linking platelet-derived growth factor (PDGF) activity to human atherosclerosis. However, no lowmolecular-weight antagonists of this growth factor have been discovered. We identified a compound, SCH 13929 (2-bromomethyl-5-chlorobenzene sulfonylphthalimide), which inhibits binding of125I-PDGF BB to cell surface receptors with an IQo of 0.13 junol/L. This compound has a lesser effect on the binding of125I-epidermal growth factor (EGF),125I-basic fibroblast growth factor (bFGF), or125I-endothelin to specific cell surface receptors. Exposure of cultured SMCs to SCH 13929 inhibits PDGF BB-and PDGF AA-stimulated DNA synthesis but not EGF-or bFGF-stimulated DNA synthesis. PDGF BB-stimulated SMC division is also inhibited by exposure to SCH 13929. Chemotaxis assays indicate that SCH 13929 inhibits PDGF-stimulated directional migration and suggest that the compound interacts with PDGF rather than with the receptor. Oral administration of SCH 13929 (100 mg/kg per day) to Sprague-Dawley rats or spontaneously hypertensive rats results in significant inhibition of lesion formation in the balloon catheter-deendothelialized carotid artery. These results suggest that SCH 13929 may be a useful tool for understanding the role of PDGF in intimal lesion formation.

ISSN:1049-8834    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

A cell culture system was employed to test a large number of samples of human serum for the ability to stimulate the efflux of cell cholesterol. The extent of efflux obtained with each specimen was correlated with the serum concentrations of cholesterol, triglycerides, apoprotein (apo) B, apo A-I, apo A-II, and lipoprotein subfractions (ie, high-density lipoprotein2[HDL2], HDL3, lipoprotein [Lp] A-I, and LpA-I:A-II). In addition, the subsequent esterification of the released cholesterol and the distribution of the synthesized exogenous cholesteryl esters between HDL and low-density lipoprotein/very-low-density lipoprotein provided estimates of the lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) activities of each serum. The values for these activities were analyzed for correlations with cell efflux and the various serum parameters. Cell cholesterol efflux best correlated with serum total HDL cholesterol values. HDL2and HDL3correlated about equally well with efflux, whereas LpA-I demonstrated a much greater association with efflux than did LpA-I:A-II. Analysis of the data by partial correlation analysis indicated that HDL3and LpA-I were the HDL subfractions most closely associated with efflux. Esterification of the released radiolabeled cholesterol was strongly and positively correlated with serum triglyceride concentrations and negatively related to the serum concentrations of HDL2. There was no relation between esterification values, which reflect LCAT activity, and efflux. The transfer of the labeled cholesteryl esters between HDL and apoB-containing lipoproteins was used as a measure of CETP activity and demonstrated a pattern in which all apoB-related parameters were positively correlated to transfer of esterified cholesterol, and all HDL associated parameters, particularly HDL3, were negatively related to transfer. No relations were observed between efflux, esterification, and transfer.

ISSN:1049-8834    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Ultrafast computed tomography (CT) is a new method for detecting calcific lesions in the coronary arteries. The ability of CT to detect and quantify coronary artery atherosclerosis in children and young adults at risk for malignant atherogenesis was evaluated. A total of 11 consecutive familial hypercholesterolemic (FH) homozygotes (3 to 37 years old) participated. Untreated total cholesterol concentrations were 488 to 1277 mg/dL (12.7 to 33.2 mmol/L). Angiography detected significant lesions in 7 of 11 patients. CT detected calcific atherosclerosis in all 9 of the patients older than 12 years of age, including all those with angina. CT was more sensitive in detecting aortic root and coronary ostial lesions, where atherosclerosis first appears in homozygous FH. The volume of calcification (in cubic millimeters) correlated with the severity and duration of the hypercholesterolemia (r=.62,P< .05) as well as with the presence of angina (P< .05). All patients with angina (7 of 7) had > 150 mm3of calcified volume, whereas only 1 of 4 asymptomatic patients had a volume score >150 mm3. We conclude that (1) coronary and aortic calcium phosphate deposits are common in young FH homozygotes; (2) these deposits are associated with the presence of angiographic stenoses, as has been seen in adults with coronary atherosclerosis; and (3) aortic calcific deposits are more common than calcific coronary lesions.

ISSN:1049-8834    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Common carotid intima-media thickness was measured by B-mode ultrasound imaging in 46 children (mean age, 7. years) with serum cholesterol 26.4 mmol/L (mean, 8.25 mmol/L) and in 48 children (mean age, 6.4 years) with serum cholesterol <6.4 mmol/L (mean, 4.60 mmol/L). Maximum thickness was significantly higher in hypercholesterolemic children than in control children (0.50 versus 0.47 mm,P= .007). Subgroup analysis showed that only in children >6.2 years old (the median of all the children's ages) was maximum thickness significantly higher in hypercholesterolemic children than in control children (0.51 versus 0.48 mm,P=.014). The odds ratio (OR) of common carotid intima-media thickening (maximum thickness of the far wall higher than the 95th percentile of the control group, 0.51 mm) between patients and control subjects was statistically significant both in univariate analysis (OR, 6.39; 95% confidence interval, 1.19 to 32.3; f>=.025) and after age (OR, 5.96; 95% confidence interval, 1.09 to 32.4;P= .039) and sex (OR, 7.54; 95% confidence interval, 1.38 to 41.2;P=.02O)were controlled for. Children >6 years old with serum cholesterol $6.4 mmol/L show increased thickness of the common carotid intima-media.

ISSN:1049-8834    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

We determined the prevalence of hyperhomocyst-(e)inemia before and 4 hours after a methionine load (3. g/m2) in 80 patients (25 men and 55 women) who had had at least one verified episode of venous thromboembolism before the age of 40 years and in 51 healthy control subjects. No patient had any of the hemostatic abnormalities known to be associated with increased risk of venous thrombosis, and all had normal renal and liver function and no evidence of neoplastic disease. Hyperhomocyst(e)inemia was defined as fasting plasma homocyst(e)ine levels or absolute postload increments of homocyst(e)ine above the normal range. According to these diagnostic criteria, 15 patients (18.8%) and 1 control subject (1.9%) had hyperhomocyst(e)inemia. In 1 of these patients only, hyperhomocyst(e)inemia could be explained by low serum concentrations of vitamin B12and folates. The family history for venous thromboembolism was positive for 7 of the 15 patients. Family studies, performed for eight kindreds, showed that for more than half of the studied probands the abnormality was inherited. This study indicates that moderate hyperhomocyst(e)inemia is associated with an increased risk of developing venous thromboembolism at a young age and that measurements of fasting and postmethionine plasma homocyst(e)ine levels may be useful in the evaluation of patients with juvenile venous thromboembolism, particularly if their family history suggests the presence of an inherited abnormality.

ISSN:1049-8834    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

We determined the common polymorphism of apolipoprotein E (E2, E3, and E4), apolipoprotein BXbaI polymorphism, and apolipoprotein C-IIISstI polymorphism in almost all Finnish centenarians alive in 1991 (n=179/185). Plasma lipid and lipoprotein levels in different apolipoprotein genotypes were also measured. In comparison with younger Finnish populations studied previously, the frequency of the apolipoprotein E e2 allele was almost twice as high (7.0% versus 4.1%;P< .05) and that of thee4allele only approximately one third as high (8.4% versus 22.7%;P< .001) in the centenarians. Plasma cholesterol and high-density lipoprotein cholesterol levels tended to be lowest in the group with the e2 allele (4.33 mmol/L and 1.41 mmol/L, respectively), intermediate in those with thee3allele (4.57 mmol/L and 1.48 mmol/L, respectively), and highest in those with theE4allele (4.82 mmol/L and 1.60 mmol/L, respectively). The frequencies of the apolipoprotein BXIandX2alleles (XbaI restriction site absent or present, respectively) among the centenarians and among the young Finns were not significantly different, whereas the apolipoprotein C-III S2 allele (SstI restriction site present) occurred more often in the centenarians (frequency, 12.9%) than in the youngest reference population (frequency, 8.8%;P< .05). Centenarians with the apolipoprotein BX2X2genotype and apolipoprotein E4 phenotype had a higher mean plasma cholesterol level than those with theX1X1genotype and E2 phenotype (5.24 versus 3.43 mmol/L;P< .05). We conclude that genetic variation of apolipoproteins influences blood lipid levels up to very high ages and that theB4allele may affect life expectancy adversely.

ISSN:1049-8834    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Coronary artery disease (CAD) patients (n=235), comprising minimal (CAD", n=124) and severe (CAD+, n=lll) CAD, were recruited on the basis of their angiographic scores. Male control subjects (n=123) were selected randomly from the Caerphilly Heart Study cohort. Subjects were genotyped for the Ser "-Ter mutation andHindlUJPvuII restriction fragment length polymorphisms of the lipoprotein lipase gene and investigated for associations with severity and development of CAD and lipid and lipoprotein levels. The Ser "-Ter mutation showed no significant associations with CAD or dyslipidemia but was related to favorable lipid and lipoprotein profiles. TheH2H2genotype (P< .05) andH2allele (P= .05) were significantly more frequent in CAD+versus CAD" and control subjects versus CAD".H2H2subjects, among the entire male cohort, had significantly higher levels of apolipoprotein B (>=.0002), total cholesterol (P< .004), and triglycerides (P< .04) than alternative genotypes.P2P2associated with significantly lower high-density lipoprotein cholesterol levels (P< .01). TheH2allele had most significant associations with raised apolipoprotein B levels compared with other biochemical parameters. Our data suggest that theH2allele may be a linkage marker for an etiologic mutation for dyslipidemia and the severity and development of atherosclerosis; this is not the Ser-Ter mutation.

ISSN:1049-8834    

出版商:OVID    

年代:1994

数据来源: OVID