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

Plasminogen activator inhibitor-1 (PAI-1) and two-chain high molecular weight kininogen (HKa) exert anti-adhesive properties in vitronectin-dependent cell adhesion. Here, the hypothesis was tested that these anti-adhesive components promote apoptosis in vascular cells. PAI-1 or HKa induced a 2- to 3-fold increase in apoptosis of human umbilical-vein endothelial cells (HUVEC) and vascular smooth muscle cells (VSMC) adherent to vitronectin, as determined by annexin V-FACS assay, similar to alphav-integrin inhibitor cyclo-(Arg-Gly-Asp-D-Phe-Val)-peptide (cRGDfV). Apoptosis occurred after 12 h incubation and was attributable to caspase 3 activation that in turn induced DNA fragmentation. Induction of apoptosis strongly correlated with the anti-adhesive effect of PAI-1 and HKa on these cells. In contrast, PAI-1 and HKa did not affect fibronectin-dependent adhesion or cell survival. uPA did not influence apoptosis in vitronectin- or fibronectin-adherent cells. In atherosclerotic vessel sections, congruent distribution of vitronectin, PAI-1, HK, and of components of the urokinase plasminogen activator/receptor system with apoptotic cells lining foam cell lesions was demonstrated by immunostaining. These results indicate that inhibition of vitronectin-dependent cell adhesion through PAI-1 and HKa correlates with apoptosis induction in vascular cells mediated through the caspase 3 pathway. Co-distribution of apoptosis with plasminogen activation system components in atherosclerosis exemplifies the significance of anti-adhesive mechanisms and apoptosis for tissue remodeling, such as in neointima development.
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PMID:Induction of apoptosis in vascular cells by plasminogen activator inhibitor-1 and high molecular weight kininogen correlates with their anti-adhesive properties. 1271 93

Oxidized low-density lipoprotein (oxLDL) is known to induce apoptosis in endothelial cells, and this is believed to contribute to the progression of atherosclerosis. In the present study we made the novel observation that oxLDL-induced death of HMEC-1 cells is accompanied by activation of calpain. The mu-calpain inhibitor PD 151746 decreased oxLDL-induced cytotoxicity, whereas the general caspase inhibitor BAF (t-butoxycarbonyl-Asp-methoxyfluoromethylketone) had no effect. Also, oxLDL provoked calpain-dependent proteolysis of cytoskeletal alpha-fodrin in the HMEC-1 cells. Our observation of an autoproteolytic cleavage of the 80 kDa subunit of mu-calpain provided further evidence for an oxLDL-induced stimulation of calpain activity. The Bcl-2 protein Bid was also cleaved during oxLDL-elicited cell death, and this was prevented by calpain inhibitors, but not by inhibitors of cathepsin B and caspases. Treating the HMEC-1 cells with oxLDL did not result in detectable activation of procaspase 3 or cleavage of PARP [poly(ADP-ribose) polymerase], but it did cause polyubiquitination of caspase 3, indicating inactivation and possible degradation of this protease. Despite the lack of caspase 3 activation, oxLDL treatment led to the formation of nucleosomal DNA fragments characteristic of apoptosis. These novel results show that oxLDL initiates a calpain-mediated death-signalling pathway in endothelial cells.
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PMID:Oxidized low-density lipoprotein induces calpain-dependent cell death and ubiquitination of caspase 3 in HMEC-1 endothelial cells. 1277 16

Magnolol, an active component extracted from Magnolia officinalis, has various pharmacological effects, including potent antioxidant activity. In the present study, we investigated the effect of magnolol on apoptosis in rat vascular smooth muscle cells (VSMCs), using terminal-deoxynucleotidyl-transferase-mediated deoxyuridine triphosphate nick end labelling (TUNEL) and flow cytometric analysis. Magnolol (5-20 micro M) concentration-dependently induced significant VSMC apoptosis, this effect being blocked by the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk, 50 micro M). To study the molecular mechanism, the mitochondrial death pathway was examined. Magnolol increased caspase-3 and caspase-9 activities significantly and reduced the mitochondrial potential (Deltapsi(m)). The levels of B-cell leukaemia/lymphoma-2 (Bcl-2), but not those of Bcl-2-associated X protein (Bax) or Bcl-x(L), were down-regulated concentration dependently by magnolol. In an animal model, balloon angioplasty-induced neointima formation was inhibited significantly by magnolol and Bcl-2 protein levels were reduced. Taken together, these results show that magnolol induces apoptosis in VSMCs via the mitochondrial death pathway. This effect is mediated through down-regulation of Bcl-2 protein levels, both in vivo and in vitro. Magnolol thus shows potential as a novel therapeutic agent for the treatment of atherosclerosis and re-stenosis.
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PMID:Magnolol induces apoptosis in vascular smooth muscle. 1289 28

Osteopontin (OPN) is a highly hydrophilic and negatively charged sialoprotein of approximately 298 amino acids that contains a Gly-Arg-Gly-Asp-Ser sequence. It is a secreted protein with diverse regulatory functions, including cell adhesion and migration, tumor growth and metastasis, atherosclerosis, aortic valve calcification, and repair of myocardial injury. Despite the many recognized functions of OPN, very little is known of the transcriptional regulation of OPN. In this regard, we have previously demonstrated that OPN transcription and promoter activity are significantly up-regulated in response to NO in a system of endotoxin-stimulated murine macrophages. However, the specific cis- and trans-regulatory elements that determine the extent of endotoxin- and NO-mediated induction of OPN synthesis are unknown. In this follow-up study, we demonstrate that: 1) OPN gene transcription is regulated by a constitutive transcriptional repressor protein, heterogeneous nuclear ribonucleoprotein A/B (hnRNP A/B); 2) inhibition of in vivo hnRNP DNA binding activity is accompanied by increased S-nitrosylation of hnRNP A/B in the setting of lipopolysaccharide (LPS)-mediated NO synthesis; 3) inhibition of LPS mediated NO synthesis restores hnRNP DNA binding and decreases the extent of S-nitrosylation; and 4) S-nitrosylation of hnRNP at cysteine 104 inhibits in vitro DNA binding activity, which is reversed by dithiothreitol. Our findings suggest that LPS induced S-nitrosylation of hnRNP inhibits its activity as a constitutive repressor of the OPN promoter and results in enhanced OPN expression.
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PMID:S-nitrosylation of heterogeneous nuclear ribonucleoprotein A/B regulates osteopontin transcription in endotoxin-stimulated murine macrophages. 2823 1

The products of nitric oxide synthase (NOS) and angiotensin-converting enzyme (ACE) play a critical role in determining vessel wall structure and function. Polymorphisms in both genes have been independently demonstrated to influence propensity to cardiovascular events. The purpose of this study was to determine the influence of the homozygous G849T (Glu298-->Asp) polymorphism in NOS III on peripheral conduit artery endothelial function and to elucidate the modifier role, if any, of a common ACE polymorphism. Three hundred and ninety-seven consecutive subjects presenting to the cardiac catheterization laboratory of the University of Michigan over a period of 18 months were recruited. DNA was extracted and polymerase chain reaction (PCR) analysis for ACE and NOS polymorphisms performed. Patients with homozygosity for G849T at both loci (TT) who belong to DD and II ACE genotype (groups 1 and 2) and those who are negative for this polymorphism (GG) and belong to either DD or II genotype (groups 3 and 4) were identified. The four groups then underwent determination of conduit endothelial function. Heterozygosity of Glu298-Asp or the ID variant of the ACE were not studied. Median FMD value in the TT-DD group was 0.20 (-3.17, 2.01) compared with 2.23% (-0.29, 4.17) in the GG-II group. Median values in the TT-II and the GG-DD groups were 3.04 (-1.16, 6.61) and 2.46% (-1.83, 6.52) respectively. These values were not statistically significant (p > 0.05 by one-way ANOVA). Median nitroglycerin-mediated dilation in the four groups did not differ between the four groups (p = NS by ANOVA). Atherosclerosis burdens as assessed by angiography were not different across the groups. In conclusion, the homozygous NOS III variant (GG) status does not seem to interact additively with the ACE homozygous DD genotype in determining flow-mediated vasodilation in individuals with established atherosclerosis and pre-existent endothelial dysfunction.
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PMID:Interactive effects of the ACE DD polymorphism with the NOS III homozygous G849T (Glu298-->Asp) variant in determining endothelial function in coronary artery disease. 1498 58

Human granzyme B (GrB) released from cytotoxic lymphocytes plays a key role in the induction of target cell apoptosis when internalized in the presence of perforin. Here we demonstrate that GrB also possesses a potent extracellular matrix remodeling activity. Both native and recombinant GrB caused detachment of immortalized and transformed cell lines, primary endothelial cells, and chondrocytes. Cell detachment by GrB induced endothelial cell death (anoikis). GrB also inhibited tumor cell spreading, migration, and invasion in vitro. Investigation into the underlying mechanism revealed that GrB efficiently cleaves three proteins involved in extracellular matrix structure and function: vitronectin, fibronectin, and laminin. In vitronectin, GrB cleaves after an Arg-Lys-Asp (RGD) motif, which is part of the integrin-binding site found in matrix proteins. We propose that targeting of the integrin-extracellular matrix interface by GrB may allow perforin-independent killing of target cells via anoikis, restrict motility of tumor cells, facilitate lymphocyte migration, or directly reduce virus infectivity. It may also contribute to tissue destruction in diseases in which extracellular GrB is evident, such as rheumatoid arthritis and atherosclerosis.
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PMID:Extracellular matrix remodeling by human granzyme B via cleavage of vitronectin, fibronectin, and laminin. 1584 72

Functional deficiency of lipoprotein lipase (LPL) was found in a patient with severe hypertriglyceridemia. The patient was 39-year-old man with a plasma triglyceride level of 2032 mg/dl, and suffered from recurrent pancreatitis. His post heparin plasma LPL mass was almost normal, but the LPL activity was remarkably decreased. Gene analysis showed that homozygote missense mutation (204 Asp (GAC)-Glu (GAG)) exists in exon 5 of LPL gene. The patient LPL purified from post heparin plasma scarcely hydrolyzed VLDL-triglyceride and also triolein emulsified with Triton X-100 or phosphatidylcholine. When phosphatidylethenolamine, phosphatidylserine and cardiolipin were used as an emulsifier for triolein, triolein-hydrolyzing activity of the patient's LPL was observed and was much higher than that of wild-type LPL. Mutant LPL gene (Asp204-Glu) was made by site-direct mutagenesis and was transfected to COS-1 cell. The expressed LPL (Asp204-Glu) also showed the same properties. These results suggested that the LPL (Asp204-Glu) is a functional deficiency, and the activity could be recovered by using acidic phospholipids as an emulsifier.
Atherosclerosis 2005 Nov
PMID:The recovery of dysfunctional lipoprotein lipase (Asp204-Glu) activity by modification of substrate. 1587 72

The Glu(298)-->Asp (E298D; 894G-->T) polymorphism of eNOS (endothelial nitric oxide synthase) has been related with cardiovascular disease. In the present study, we investigated the association of Glu(298)-->Asp with atherosclerotic plaques in different carotid vessel segments and with carotid IMT (intima-media thickness). The Glu(298)-->Asp eNOS polymorphism was determined by 5'-exonuclease assay among 2448 participants of the SHIP (Study of Health in Pomerania). Mean and maximum common carotid IMT, as well as carotid atherosclerosis, were measured by high-resolution ultrasound. The Asp/Asp(298) genotype was associated with an increased risk of atherosclerotic plaques at the level of the common carotid arteries [multivariate odds ratio, 1.57 and 95% CI (confidence interval), 1.05-2.34; P=0.025], but not in the carotid bifurcations or internal or external carotid arteries. Glu(298)-->Asp genotype was not associated with carotid IMT in the whole sample. However, the Asp/Asp(298) genotype was independently associated with both higher mean [adjusted increase by 0.046 mm (95% CI, 0.013-0.078); P=0.006] and maximum carotid IMT [0.137 mm (95% CI, 0.064-0.209); P<0.001] in the low-risk group of subjects without carotid atherosclerosis. In conclusion, the Asp/Asp(298) genotype is associated with atherosclerosis in the common carotid arteries and, in a low-risk group, also with carotid IMT. This suggests that the association of the Glu(298)-->Asp genotype with atherosclerosis in the carotid arteries is site-specific and is modified by overall cardiovascular risk.
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PMID:Endothelial nitric oxide synthase Glu(298)-->Asp polymorphism, carotid atherosclerosis and intima-media thickness in a general population sample. 1606 Aug 60

Oxidized low-density lipoprotein (Ox-LDL) is known to be involved in the generation and progression of atherosclerosis. Ox-LDL has a number of potentially atherogenic effects on vascular cells, including uncontrol uptake by scavenger receptors. Asp-hemolysin, a hemolytic toxin from Aspergillus fumigatus, is a binding protein for Ox-LDL. This study was undertaken to clarify the binding specificity of Asp-hemolysin to Ox-LDL. We examined the binding specificity of Asp-hemolysin to Ox-LDL using several modified lipoproteins and scavenger-receptor ligands. Asp-hemolysin bound to Ox-LDL with shorter LDL oxidation times. However, Asp-hemolysin did not bind to acetylated LDL. The native high-density lipoprotein (n-HDL) and modified HDL (e.g., acetylated HDL, oxidized HDL) also had no Asp-hemolysin binding. Inhibitors of scavenger-receptor binding, including maleylated bovine serum albumin, polyinosinic acid, dextran sulfate, and fucoidin, had no effect on the binding of Ox-LDL to Asp-hemolysin. Surface plasmon-resonance studies revealed that Ox-LDL binds with high affinity (K(D)=0.63 microg/ml) to Asp-hemolysin. Furthermore, we have shown that Ox-LDL strongly inhibits the hemolytic activity of Asp-hemolysin and that the removal of lysophosphatidylcholine (lysoPC) from Ox-LDL abolished the inhibition. We also investigated the interaction between Asp-hemolysin and lysoPC as a typical lipid moiety of Ox-LDL. The binding of Asp-hemolysin to LDL oxidized for different times depended on the lysoPC content in each Ox-LDL. In addition, the inhibition of lysoPC production in Ox-LDL by phenylmethylsulfonyl fluoride (PMSF) pretreatment of LDL resulted in a marked decrease in Asp-hemolysin binding to PMSF-pretreated Ox-LDL. The binding analysis of Asp-hemolysin to lysoPC revealed that Asp-hemolysin binds directly to lysoPC. We conclude that Asp-hemolysin is a specific binding protein with high affinity for Ox-LDL and that its binding specificity is distinct from any receptor for Ox-LDL.
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PMID:[Binding Characterizations of Asp-hemolysin to Oxidized Low-Density Lipoprotein]. 1607 12

Interactions of leukocytes with the vascular endothelium culminating in their diapedesis represent not only a crucial event in immune surveillance and defense but are also critically involved in the pathogenesis of many inflammatory diseases, including atherosclerosis. Our previous in vitro studies using atomic force microscopy measurement of monocyte-endothelial cell interaction have demonstrated that a cyclic arginine-glycine-aspartic acid peptide (cRGD) inhibited their adhesion through very late antigen (alpha4beta1-integrin; VLA4)-vascular cell adhesion molecule-1 by 60% with the IC50 = 100 nM. To elucidate the potential efficacy of this peptide in vivo in preventing atherogenesis, experiments were performed in apolipoprotein E (ApoE)-deficient (-/-) mice fed a Western diet and receiving chronic treatment with cRGD peptide for 2-4 wk. In addition, some animals were subjected to a temporary carotid artery ligation while receiving the above treatment. Formation of fatty streaks and infiltration of the vascular wall with macrophages were not affected by cRGD treatment. Infiltration of the carotid artery postligation was significantly reduced in the cRGD-treated animals, as was the lipid accumulation. Furthermore, cRGD-treated ApoE-/- mice exhibited significantly lesser macrophage infiltration and lipid accumulation in the kidneys, the site of the highest expression of VLA4. These data demonstrated that cRGD peptide is a potent inhibitor of monocyte/macrophage infiltration of the injured macrovasculature and of the renal microvasculature, where it results in the attenuation of lipid accumulation. Formation of fatty streaks in the aortic root was not inhibitable by this treatment.
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PMID:Cyclic arginine-glycine-aspartic acid peptide inhibits macrophage infiltration of the kidney and carotid artery lesions in apo-E-deficient mice. 1610 36


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