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Subroto Chatterjee

Publications and source records attributed to Subroto Chatterjee.

At least 19 recordsLinked to original sources
PubMed2006

MRI visualized neo-intimal dissection and co-localization of novel apoptotic markers apolipoprotein C-1, ceramide and caspase-3 in a Watanabe hyperlipidemic rabbit model.

PURPOSE: Apoptotic arterial wall vascular smooth muscle cell death is known to contribute to plaque vulnerability and rupture. Novel apoptotic markers like apolipoprotein C-I have been implicated in apoptotic human vascular smooth muscle cell death via recruiting a neutral sphingomyelinase (N-SMase)-ceramide pathway. In vivo relevance of these observations in an animal model of plaque rupture has not been shown. METHODS AND RESULTS: Using Watanabe rabbits, we investigated three different groups (group 1, three normal Watanabe rabbits; group 2, six Watanabe rabbits fed with high cholesterol diet for 3 months; group 3, five Watanabe rabbits with similar diet but additional endothelial denudation). We followed progression of atherosclerosis to pharmacologically induced plaque rupture non-invasively using novel 3D magnetic resonance Fast-Field-Echo angiography (TR=7.2, TE=3.6 ms, matrix=512 x 512) and Fast-Spin-Echo vessel wall imaging methods (TR=3 heart beats, TE=10.5 ms, matrix=304 x 304) on 1.5 T MRI. MRI provided excellent image quality with good MRI versus histology vessel wall thickness correlation (r=0.8). In six animals of group 2/3 MRI detected neo-intimal dissection in the abdominal aorta which was accompanied by immuno-histochemical demonstration of concomitant aforementioned novel apoptotic markers, previously implicated in the apoptotic smooth muscle cell death in vitro. CONCLUSIONS: Our studies suggest a potential role for the signal transduction pathway involving apolipoprotein C-I for in vivo apoptosis and atherosclerotic plaque rupture visualized by MRI.

Animals↗
PubMed2006

Lactosylceramide is required in apoptosis induced by N-Smase.

Lactosylceramide (LacCer) is a member of the glycosphingolipid family which has been recently recognized as a signaling intermediate in the regulation of cell proliferation and cell adhesion. In this paper, we present our studies pointing to a potential role of LacCer in inducing apoptosis. In our studies we employed a human osteosarcoma cell line MG-63 (wild type, WT) and a neutral sphingomyelinase (N-SMase) deficient cell line CC derived from MG-63 (mutant) cells. We observed that WT cells were highly sensitive to tumor necrosis factor-alpha (TNF-alpha), ceramide and LacCer-induced apoptosis. In contrast, the mutant cells were insensitive to TNF-alpha-induced apoptosis as they did not generate ceramide and LacCer. However, the exogenous supply of ceramide and/or LacCer rendered the mutant cells apoptotic. Interestingly, preincubation of cells with D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), an inhibitor of glucosylceramide synthase and lactosylceramide synthase, abrogated ceramide-induced apoptosis but not LacCer-induced apoptosis in both WT cells and the mutant cells. Moreover, TNF-alpha and LacCer-induced apoptosis required the generation of reactive oxygen species (ROS) in WT cells. However, since mutant cells did not produce significant amounts of LacCer and ROS in response to TNF-alpha treatment they are insensitive to TNF-alpha-induced apoptosis. In summary, our studies suggest that TNF-alpha-induced N-SMase activation and production of ceramide is required to activate the apoptosis pathway in human osteosarcoma cells. But it is not sufficient to induce apoptosis. Rather, the conversion of ceramide to LacCer and ROS generation are critical for apoptosis.

Apoptosis↗
PubMed2006

The role of the phospholipid sphingomyelin in heart disease.

Sphingomyelin (SM) is an integral component of mammalian cell membranes and nerves. However, the inability to catabolize SM may lead to its accumulation in various tissues and organs, resulting in pathological disorders such as Niemann Pick disease. Elevated levels of SM have also been identified as an independent risk factor for coronary heart disease. During the past two decades, data have emerged that support an important role for metabolites of SM, such as ceramide and sphingosine-1-phosphate, in the regulation of phenotypic changes such as cell proliferation, cell-cycle arrest, apoptosis and angiogenesis. Further studies of the molecular and pathobiological basis of these phospholipids may facilitate advances in the discovery of drugs with which to mitigate diseases that may result from an elevation in SM and its metabolites.

Animals↗
PubMed2005

Novel role of lactosylceramide in vascular endothelial growth factor-mediated angiogenesis in human endothelial cells.

Vascular endothelial growth factor (VEGF) has been implicated in angiogenesis associated with coronary heart disease, vascular complications in diabetes, inflammatory vascular diseases, and tumor metastasis. The mechanism of VEGF-driven angiogenesis involving glycosphingolipids such as lactosylceramide (LacCer), however, is not known. To demonstrate the involvement of LacCer in VEGF-induced angiogenesis, we used small interfering RNA (siRNA)-mediated silencing of LacCer synthase expression (GalT-V) in human umbilical vein endothelial cells. This gene silencing markedly inhibited VEGF-induced platelet endothelial cell adhesion molecule-1 (PECAM-1) expression and angiogenesis. Second, we used D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), an inhibitor of LacCer synthase and glucosylceramide synthase, that significantly mitigated VEGF-induced PECAM-1 expression and angiogenesis. Interestingly, these phenotypic changes were reversed by LacCer but not by structurally related compounds such as glucosylceramide, digalactosylceramide, and ceramide. In a human mesothelioma cell line (REN) that lacks the endogenous expression of PECAM-1, VEGF/LacCer failed to stimulate PECAM-1 expression and tube formation/angiogenesis. In REN cells expressing human PECAM-1 gene/protein, however, both VEGF and LacCer-induced PECAM-1 protein expression and tube formation/angiogenesis. In fact, VEGF-induced but not LacCer-induced angiogenesis was mitigated by SU-1498, a VEGF receptor tyrosine kinase inhibitor. Also, VEGF/LacCer-induced PECAM-1 expression and angiogenesis was mitigated by protein kinase C and phospholipase A2 inhibitors. These results indicate that LacCer generated in VEGF-treated endothelial cells may serve as an important signaling molecule for PECAM-1 expression and in angiogenesis. This finding and the reagents developed in our report may be useful as anti-angiogenic drugs for further studies in vitro and in vivo.

Cells, Cultured↗
PubMed2005

Radiofrequency-enhanced vascular gene transduction and expression for intravascular MR imaging-guided therapy: feasibility study in pigs.

PURPOSE: To evaluate the feasibility of radiofrequency (RF)-enhanced vascular gene transduction and expression by using a magnetic resonance (MR) imaging-heating guidewire as an intravascular heating vehicle during MR imaging-guided therapy. MATERIALS AND METHODS: The institutional committee for animal care and use approved the experimental protocol. The study included in vitro evaluation of the use of RF energy to enhance gene transduction and expression in vascular cells, as well as in vivo validation of the feasibility of intravascular MR imaging-guided RF-enhanced vascular gene transduction and expression in pig arteries. For in vitro experiments, approximately 10(4) vascular smooth muscle cells were seeded in each of four chambers of a cell culture plate. Next, 1 mL of a green fluorescent protein gene (gfp)-bearing lentivirus was added to each chamber. Chamber 4 was heated at approximately 41 degrees C for 15 minutes by using an MR imaging-heating guidewire connected to a custom RF generator. At day 6 after transduction, the four chambers were examined and compared at confocal microscopy to determine the efficiency of gfp transduction and expression. For the in vivo experiments, a lentivirus vector bearing a therapeutic gene, vascular endothelial growth factor 165 (VEGF-165), was transferred by using a gene delivery balloon catheter in 18 femoral-iliac arteries (nine artery pairs) in domestic pigs and Yucatan pigs with atherosclerosis. During gene infusion, one femoral-iliac artery in each pig was heated to approximately 41 degrees C with RF energy transferred via the intravascular MR imaging-heating guidewire, while the contralateral artery was not heated (control condition). At day 6, the 18 arteries were harvested for quantitative Western blot analysis to compare VEGF-165 transduction and expression efficiency between RF-heated and nonheated arterial groups. RESULTS: Confocal microscopy showed gfp expression in chamber 4 that was 293% the level of expression in chamber 1 (49.6% +/- 25.8 vs 16.8% +/- 8.0). Results of Western blot analysis showed VEGF-165 expression for normal arteries in the RF-heated group that was 300% the level of expression in the nonheated group (70.4 arbitrary units [au] +/- 107.1 vs 23.5 au +/- 29.8), and, for atherosclerotic arteries in the RF-heated group, 986% the level in the nonheated group (129.2 au +/- 100.3 vs 13.1 au +/- 4.9). CONCLUSION: Simultaneous monitoring and enhancement of vascular gene delivery and expression is feasible with the MR imaging-heating guidewire.

Animals↗
PubMed2005

Statin-inhibited endothelial permeability could be associated with its effect on PECAM-1 in endothelial cells.

UNLABELLED: The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are known to inhibit leukocyte recruitment to endothelium but the mechanism is less understood. Platelet endothelial cell adhesion molecule-1 (PECAM-1) is an endothelial junction protein involved in leukocyte diapedesis. We hypothesize that in endothelial cells, statins may well recruit PECAM-1 to exert their inhibitory effect on leukocyte trans-endothelial migration (TEM). In lovastatin-treated resting human umbilical vein endothelial cells (HUVECs), increased levels of mRNA and protein of PECAM-1 as well as its bio-synthesis (all approximately 2-fold) were observed by real-time PCR, Western blotting and 35S-labeled methionine incorporation assay, respectively. Moreover, in lovastatin treated resting cells as well as TNF-alpha activated endothelial cells, unanimously decreased Triton X-100 insoluble and soluble PECAM-1 ratio was observed. Such changes were accompanied by decreased TEM of U-937 cells (a promonocyte cell line). All lovastatin's effects were abrogated by mevalonic acid. In resting HUVECs, geranylgeranyl pyrophosphate (GGPP), but not farnesyl pyrophosphate (FPP) (both are isoprenoid intermediates in the cholesterol biosynthesis pathway) compromised the effect of lovastatin on PECAM-1 expression, whereas C3 toxin, an inhibitor of small G proteins, exerted statin-like effect. CONCLUSION: Statin-reduced endothelial permeability could be attributed to altered intracellular distribution of PECAM-1 in endothelial cells. We speculate that lovastatin regulates PECAM-1 expression in HUVECs through the mevalonate-GGPP pathway by inhibiting of Rho small GTPase.

Cells, Cultured↗
PubMed2005

Platelet derived growth factor recruits lactosylceramide to induce cell proliferation in UDP Gal:GlcCer: beta1 --> 4Galactosyltransferase (GalT-V) mutant Chinese hamster ovary cells.

Recent molecular cloning studies have suggested the presence of at least two beta4Gal transferase genes (beta4GalT-V and beta4GalT-VI) that may encode lactosylceramide synthase but whether they are functional in vivo and whether they mediate growth factor induced phenotypic change such as cell proliferation is not known. Our previous studies lead to the suggestion that various risk factors in atherosclerosis such as oxidized LDL, shear stress, nicotine, tumor necrosis factor-alpha converge upon LacCer synthase to induce critical phenotypic changes such as cell proliferation and cell adhesion. However, whether platelet-derived growth factor also recruits LacCer synthase in mediating cell proliferation is not known. Here we have employed a Chinese hamster ovary mutant cell line Pro(-)5Lec20 to determine whether this enzyme physiologically functions to mediate cell proliferation. We show that PDGF stimulates the activity of UDP galactose:glucosylceramide, beta1,4galactosyltransferase. The activity of LacCer synthase increased about 2.5 fold within 2.5-5 min of incubation with PDGF in both wild type and Pro(-)5Lec20 cells. Concomitantly, there was an increase in the generation of superoxide radicals, p44MAPK phosphorylation and cell proliferation in CHO cells. D-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), a potent inhibitor of GlcCer synthase/LacCer synthase impaired PDGF mediated induction of LacCer synthase activity, superoxide generation, p44 MAPK activation and cell proliferation in Pro(-)5Lec20 cells. PDGF-induced superoxide generation was also mitigated by the use of diphenylene iodonium; an inhibitor of NADPH oxidase activity that is required for superoxide generation. This inhibition was bypassed by the addition of lactosylceramide. Thus, beta4GalT-V gene produces a bona fide LacCer synthase that can function in vivo to generate LacCer. Moreover, this enzyme alone can mediate PDGF induced activation of a signal transduction cascade involving superoxide generation, p44MAPK activation, phosphorylation of Akt and cell proliferation.

Animals↗
PubMed2005

Rac1 inhibition protects against hypoxia/reoxygenation-induced lipid peroxidation in human vascular endothelial cells.

Both in vivo models of ischemia/reperfusion and in vitro models of hypoxia (H)/reoxygenation (R) have demonstrated the crucial role of the Rac1-regulated NADPH oxidase in the production of injurious reactive oxygen species (ROS) by vascular endothelial cells (ECs). Since membrane lipid peroxidation has been established as one of the mechanisms leading to cell death, we examined lipid peroxidation in H/R-exposed cultured human umbilical vein ECs (HUVECs) and the role of Rac1 in this process. H (24 h at 1% O2)/R (5 min) caused an increase in intracellular ROS production compared to a normoxic control, as measured by dichlorofluorescin fluorescence. Nutrient deprivation (ND; 24 h), a component of H, was sufficient to induce a similar increase in ROS under normoxia. Either H(24 h)/R (2 h) or ND (24 h) induced increases in lipid peroxidation of similar magnitude as measured by flow cytometry of diphenyl-1-pyrenylphosphine-loaded HUVECs and Western blotting analysis of 4-hydroxy-2-nonenal-modified proteins in cell lysates. In cells infected with a control adenovirus, H (24 h)/R (2 h) and ND (24 h) resulted in increases in NADPH-dependent superoxide production by 5- and 9-fold, respectively, as measured by lucigenin chemiluminescence. Infection of HUVECs with an adenovirus that encodes the dominant-negative allele of Rac1 (Rac1N17) abolished these increases. Rac1N17 expression also suppressed the H/R- and ND-induced increases in lipid peroxidation. In conclusion, ROS generated via the Rac1-dependent pathway are major contributors to the H/R-induced lipid peroxidation in HUVECs, and ND is able to induce Rac1-dependent ROS production and lipid peroxidation of at least the same magnitude as H/R.

Adenoviridae↗
PubMed2005

Association of Leu125Val polymorphism of platelet endothelial cell adhesion molecule-1 (PECAM-1) gene & soluble level of PECAM-1 with coronary artery disease in Asian Indians.

BACKGROUND & OBJECTIVES: Platelet endothelial cell adhesion molecule-1 (PECAM-1) plays a key role in the transendothelial migration of circulating leukocytes (diapedesis) during vascular inflammation. We hypothesized that genetic variation and the level of soluble PECAM-1 could be associated with the development of atherosclerosis and conducted a study on gene polymorphisms of PECAM-1 and soluble PECAM-1 levels in Asian Indian patients with coronary artery disease (CAD) in Singapore. METHODS: Of the 137 angiographically confirmed patients (> or =70% stenosis) of CAD and 110 controls in Asian Indian population, two single nucleotide polymorphisms (SNPs) of PECAM-1 gene, C+373G (Leu125Val) at exon 3 and G+1688A (Ser563Asn) at exon 8 were analyzed by polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) strategy. In addition, plasma soluble PECAM-1, P-selection and lipid profile were measured. Chi- square test and student t test were adopted to compare categorical and continuous variables, respectively. RESULTS: A significant decrease in C allele frequency but increase in G allele frequency of the Leu125Val (C/G) polymorphism were observed in CAD patients as compared with controls (0.54/0.46 vs 0.663/0.337 respectively, P=0.008). Alteration in genotype distributions (CC, CG and GG) of the Leu125Val polymorphism between CAD patients and controls (P=0.009) was also significant. A similar trend was observed on the allele frequencies (G/A) and genotype distributions of Ser563Asn (G/A) polymorphism, though the difference did not reach significance. On the other hand, plasma level of soluble PECAM-1 (sPECAM-1) was markedly elevated in CAD patients (P=0.006), and associated with soluble P-selectin and lipid profiles. INTERPRETATION & CONCLUSION: Our study showed that Leu125Val polymorphism of PECAM-1 gene and elevated soluble PECAM-1 were related to severe coronary artery stenosis in CAD patients of Asian Indian origin in Singapore. Our data also suggest that PECAM-1 plays an important role in the development of atherosclerosis.

Base Sequence↗
PubMed2004

Identification of a novel transcript of human PECAM-1 and its role in the transendothelial migration of monocytes and Ca2+ mobilization.

Platelet-endothelial cell adhesion molecule-1 (PECAM-1) is an integral component of endothelial cells and has been implicated in the transendothelial migration (TEM) of circulating leukocytes mediated by its 1st and 2nd extracellular immunoglobulin (Ig)-like domains and regulation of intracellular Ca(2+) homeostasis with its 6th domain. Up-to-date, little is known about the role of the 5th extracellular (Ig)-like domain. We have discovered a novel human PECAM-1 transcript missing the entire 7th exon, which encodes the 5th extracellular (Ig)-like domain of PECAM-1. A synthetic peptide with sequence homology to the 5th domain of PECAM-1 (JHS-7 peptide) and a corresponding polyclonal antibody (JHS-7 Ab) were prepared and their potential role in transendothelial migration and Ca(2+) influx was measured. The JHS-7 peptide and the antibody exerted a dose dependent decrease (50-80%) in the transendothelial migration of freshly isolated human monocytes and a promonocytic cell line (U-937) in resting HUVECs and HUVECs activated with tumor necrosis factor-alpha. This was accompanied by an increase in Ca(2+) influx and decrease in refilling of the intracellular Ca(2+) stores in HUVECs. In summary, we have identified a novel PECAM-1 transcript (Deltaexon 7) and shown that the 5th (Ig)-like domain of PECAM-1 plays a role in monocyte TEM and Ca(2+) homeostasis.

Amino Acid Sequence↗
PubMed2004

Lactosylceramide recruits PKCalpha/epsilon and phospholipase A2 to stimulate PECAM-1 expression in human monocytes and adhesion to endothelial cells.

Despite the importance of platelet/endothelial cell adhesion molecule-1 (PECAM-1, CD31) in the adhesion and diapedesis of monocytes/lymphocytes, little is known about the mechanisms by which it is regulated. We explored the role of a glycosphingolipid, lactosylceramide (LacCer), in modulating PECAM-1 expression and cell adhesion in human monocytes. We observed that LacCer specifically exerted a time-dependent increase in PECAM-1 expression in U-937 cells. Maximal increase in PECAM-1 protein occurred after incubation with LacCer for 60 min. LacCer activated PKCalpha and -epsilon by translocating them from cytosol to membrane. This was accompanied by the activation of phospholipase A(2) (PLA(2)) and the increase of cell adhesion, which were abrogated by chelerythrine chloride, 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide and 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole (GO 6976) (PKC inhibitors). Similarly, bromoenol lactone (a Ca(2+)-independent PLA(2) inhibitor) and methyl arachidonyl fluorophosphonate (an inhibitor of cytosolic PLA(2) and Ca(2+)-independent PLA(2)) inhibited LacCer-induced PLA(2) activity. Bromophenacyl bromide (a PLA(2) inhibitor) abrogated LacCer-induced PECAM-1 expression, and this was bypassed by arachidonic acid. Furthermore, the arachidonate-induced up-regulation of PECAM-1 was abrogated by indomethacin [a cyclooxygenase (COX)-1 and -2 inhibitor] or N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (a COX-2 inhibitor) but not nordihydroguaiaretic acid (a lipoxygenase inhibitor). In sum, PKCalpha/epsilon are the primary targets for the activation of LacCer. Downstream activation of intracellular Ca(2+)-independent PLA(2) and/or cytosolic PLA(2) results in the production of arachidonic acid, which in turn serves as a precursor for prostaglandins that subsequently stimulate PECAM-1 expression and cell adhesion. These findings may be relevant in explaining the role of LacCer in the regulation of PECAM-1 and related pathophysiology.

Animals↗
PubMed2004

Platelet-endothelial cell adhesion molecule-1 gene polymorphism and its soluble level are associated with severe coronary artery stenosis in Chinese Singaporean.

OBJECTIVES: Platelet-endothelial cell adhesion molecule-1 (PECAM-1) mediates the transendothelial migration of circulating leukocytes, a characteristic change in vascular inflammation leading to atherosclerotic plaque development. We hypothesized that genetic variation and soluble level of PECAM-1 could be associated with coronary artery disease (CAD). DESIGN AND METHODS: We analyzed two single nucleotide polymorphisms (SNPs) of PECAM-1 gene C+373G (Leu125Val) at exon 3, which encodes the first extracellular (Ig)-like domain that mediates the homophilic binding of PECAM-1, and G+1688A (Ser563Asn) at exon 8 in 144 angiographically documented (> or =70% stenosis) patients with CAD and 150 age- and sex-matched controls in the Chinese population in Singapore, using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) strategy. Level of plasma soluble PECAM-1 (sPECAM-1) was measured by ELISA. RESULTS: The Leu125Val polymorphism was associated with CAD (P < 0.01). Also, the level of sPECAM-1 is was found to be elevated in CAD patients (P = 0.005). Moreover, subjects with the homozygous GG genotype of the Leu125Val polymorphism had higher sPECAM-1 levels (P = 0.005). The level of sPECAM-1 was further correlated to soluble platelet selectin (sP-selectin, also measured by ELISA), platelet count, and total white blood cell count (WBC), suggesting that platelets are a major source of sPECAM-1 and platelet activation and inflammation may contribute to PECAM-1 elevations in CAD patients. CONCLUSION: The Leu125Val polymorphism of PECAM-1 and the level of sPECAM-1 are associated with CAD in Chinese in Singapore. The level of sPECAM-1 is also associated with platelet activation and inflammation and correlated to the Leu125Val polymorphism. Our data suggest that PECAM-1 plays an important role in the development of atherosclerosis.

Arteriosclerosis↗
PubMed2004

Identification of a biologically active component in minimally oxidized low density lipoprotein (MM-LDL) responsible for aortic smooth muscle cell proliferation.

Although low concentrations (10 microg/ml) of oxidized LDL density lipoproteins (Ox-LDL) and minimally modified LDL (MM-LDL) can stimulate the proliferation of aortic smooth muscle cells the biologically active component responsible for this phenomena has not been identified. Here we report that the 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-4-phosphocholine (m/e594.3) (POVPC) present in MM-LDL but not 1-palmitoyl-2-glutaryl-sn-glycero-3-phophochline (m/e610.2)(PGPC) can stimulate the activity of UDP-galactose:glucosylceramide (beta 1-->4) galactosyltransferase (GalT-2) and produce lactosyceramide (LacCer). LacCer, in turn, generated superoxide radicals (O(2)(.-)). This is accompanied by the phosphorylation/activation of a cytosolic transcriptional factor p(44) MAPK and the subsequent proliferation of human aortic smooth muscle cells. D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), an inhibitor of GalT-2, impaired the induction of GalT-2 activity, O(2)(.-)generation, and cell proliferation. Thus POVPC may serve as a surrogate in MM-LDL mediated induction of aortic smooth muscle cells (A-SMC) proliferation via GalT-2 activation. The LacCer produced as a consequence of GalT-2 activation may serve as a lipid second messenger in the activation of an oxidant sensitive transcriptional pahtway that ultimately leads to cell proliferation and may contribute to the pathophysiology of atherosclerosis.

Aorta↗
PubMed2004

Markers of low-grade inflammation and soluble cell adhesion molecules in Chinese patients with coronary artery disease.

BACKGROUND: Inflammation plays an important role in atherosclerosis. Markers of low-grade chronic inflammation, such as C-reactive protein (CRP) and soluble cell adhesion molecules (sCAMs), have been associated with coronary artery disease (CAD). OBJECTIVE: To evaluate the significance of inflammatory markers as novel risk factors for CAD in the Chinese population. METHODS: High-sensitivity CRP (hs-CRP); sCAMs, including vascular cell adhesion molecule-1 (sVCAM-1), intercellular cell adhesion molecule-1 (sICAM-1), P-selectin (sP-selectin) and E-selectin (sE-selectin); and white blood cell (WBC) count were measured in 170 angiographically defined CAD patients (70% or greater stenosis affecting at least one vessel) and 177 healthy control subjects in the Chinese population in Singapore. RESULTS: The levels of hs-CRP, sVCAM-1 and sP-selectin, and the WBC count were higher in CAD patients than in control subjects (P<0.001, P<0.05, P<0.05 and P<0.001, respectively). There were no significant differences in the levels of sICAM-1 and sE-selectin between the two groups. Patients with unstable angina or myocardial infarction had higher levels of hs-CRP, and higher WBC and monocyte counts than those with stable angina or atypical chest pain (all P<0.05). The level of sP-selectin in patients with multivessel disease was higher than in those with single-vessel disease (P<0.05). Overall, the levels of hs-CRP and sCAMs showed a significant correlation with the lipid profile and the WBC count. CONCLUSIONS: The present study suggests that inflammatory markers, including hs-CRP and WBC count, together with sP-selectin and sVCAM-1, could serve as markers of atherogenesis in Chinese patients with CAD, with potential diagnostic and therapeutic implications.

Aged↗
PubMed2003

Apolipoprotein C-I induces apoptosis in human aortic smooth muscle cells via recruiting neutral sphingomyelinase.

OBJECTIVE: Apolipoprotein C-I (apoC-I) influences lipoprotein metabolism, but little is known about its cellular effects in aortic smooth muscle cells (ASMC). METHODS AND RESULTS: In cultured human ASMC, apoC-I and immunoaffinity purified apoC-I-enriched high-density lipoproteins (HDL) markedly induced apoptosis (5- to 25-fold), compared with control cells, apoC-I-poor HDL, and apolipoprotein C-III (apoC-III) as determined by 4', 6-diamidino-2-phenylindole dihydrochloride staining and DNA ladder assay. Preincubation of cells with GW4869, an inhibitor of neutral sphingomyelinase (N-SMase), blocked apoC-I-induced apoptosis, an effect that was bypassed by C-2 ceramide. The activity of N-SMase was increased 2- to 3-fold in ASMC by apoC-I, apoC-I-enriched HDL, and tumor necrosis factor alpha (TNF-alpha) (positive control) after 10 minutes and then decreased over 60 minutes, which is a kinetic pattern not seen with controls, apoC-III, and apoC-I-poor HDL. ApoC-I and apoC-I-enriched HDL stimulated the generation of ceramide, the release of cytochrome c from mitochondria, and activation of caspase-3 greater than that found in controls, apoC-III, and apoC-I-poor HDL. GW4869 inhibited apoC-I-induced production of ceramide and cytochrome c release. CONCLUSIONS: ApoC-I and apoC-I-enriched HDL activate the N-SMase-ceramide signaling pathway, leading to apoptosis in human ASMC, which is an effect that may promote plaque rupture in vivo.

Aniline Compounds↗