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)

1. Hyperglycaemia is believed to be a major cause of diabetic vascular complications such as accelerated atherosclerosis. In order to elucidate the effect of hyperglycaemia on vascular response in spontaneously hypertensive rats (SHR), the natriuretic peptides receptor responses to vascular smooth muscle cells (VSMC) which are thought to suppress atherosclerosis were studied under high glucose (HG:22.2 mmol/L) conditions. 2. The total number of cells in SHR is higher and natriuretic peptides receptor response is smaller than that of cells in the Wistar-Kyoto (WKY) rat. Membrane bound protein kinase C (PKC) activity in HG or SHR is higher compared to that of cells in normal glucose (NG:5.6 mmol/L) or WKY. Cells cultured in HG for at least 2 passages had higher total cell number and receptor mediated cGMP formation were suppressed compared to cells cultured in NG both in SHR and WKY. Specific PKC inhibitor PKC (19-36) 1 mu mol/L prevented HG induced suppression of natriuretic peptides response. 3. These results show that hyperglycaemia may be linked to suppressed natriuretic peptides receptor response which is caused by increased PKC activity both in WKY and SHR. This suppressed response may cause the accelerated atherosclerosis by hyperglycaemia.
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PMID:Elevated glucose concentration and natriuretic peptides receptor response on vascular smooth muscle of spontaneously hypertensive rats. 907 46

The involvement of inflammatory mechanisms in the progression of atherosclerosis has recently been suggested. Monocyte chemotactic protein 1 (MCP-1) is a soluble protein which is implicated in acute and chronic inflammatory processes, including atherosclerosis. We evaluated the effect of human recombinant MCP-1 on the in vitro proliferation of rat vascular smooth muscle cells (VSMCs). Incubation of VSMCs with MCP-1 (50-200 ng/ml) in the presence of 0.5% FCS significantly increased cell proliferation, [3H]-thymidine incorporation and the proliferative S fraction, measured by flow cytometry, compared to control cells. The proliferative effect of MCP-1 was specific, as shown by inhibition with a rabbit polyclonal serum to MCP-1. Moreover, the mitogenic effect of MCP-1 was significantly inhibited by downregulation of protein kinase C (PKC) activity and by incubation with H-7, a protein kinase inhibitor, suggesting the involvement of the PKC system. Verapamil, a Ca2+ channel blocker, also reduced the stimulatory effect of MCP-1 on cell proliferation. This study demonstrates that MCP-1 does not merely have a chemotactic activity, but also a mitogenic effect on cultured rat VSMCs.
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PMID:Monocyte chemotactic protein 1 (MCP-1) is a mitogen for cultured rat vascular smooth muscle cells. 907 26

Proliferation of vascular smooth muscle cells (SMCs) is implicated in pathological events, including atherosclerosis and intimal hyperplasia following angioplasty. The glycosaminoglycan heparin is a growth inhibitor of SMCs in vitro and in vivo. The underlying mechanism, however, is still poorly understood. In the present study, we report that heparin inhibited the activation of the mitogen-activated protein kinase (MAPK) in baboon SMCs by serum but not by platelet-derived growth factor (PDGF). When fibroblast growth factor was used, heparin had a stimulatory effect on MAPK. The only MAPK-activating kinase found in SMCs was MAPK kinase (MAPKK)-1, although MAPKK-2 was present in comparable amounts. Activation of MAPKK-1 and DNA synthesis were affected by heparin in a similar fashion. Heparin does not appear to exert its effects through members of the protein kinase C family, which are downregulated by phorbol esters, because it was still capable of inhibiting MAPK/MAPKK-1 stimulation by FCS in phorbol ester-pretreated cells. The present findings support the conclusions that the effects of heparin depend on the nature of the mitogen and that heparin inhibits SMC proliferation by preventing activation of MAPKK-1.
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PMID:Diverse effects of heparin on mitogen-activated protein kinase-dependent signal transduction in vascular smooth muscle cells. 920 Oct 23

Hyperhomocysteinemia has been recognized as an independent risk factor for cerebral, coronary, and peripheral atherosclerosis. To examine the contribution of homocysteine (H[cys]) in the pathogenesis of vascular diseases, we sought to determine whether the H[cys] effect on vascular smooth muscle (VSMC) proliferation is mediated by a specific receptor/transporter or is due to an interaction with growth factors or cytokines. We show that H[cys] induced c-fos and c-myb and increased DNA synthesis and cell proliferation 12-fold in neural crest-derived VSMC (N-VSMC). The H[cys] effect on N-VSMC proliferation is inhibited by Mk-801, a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, a glutamate-gated calcium ion channel receptor, and CGS 19755, a competitive antagonist of NMDA-type glutamate receptor. H[cys] stimulates the synthesis of mass amounts of sn-1,2 diacylglycerol, and activates protein kinase C translocation from the nucleus and cytoplasm to cell membranes. Furthermore, protein kinase C inhibitors block the growth effect mediated by H[cys]. These findings indicate that H[cys]-mediated responses are coupled to diacylglycerol-dependent protein kinase C activation. Our results suggest that homocysteine activates a receptor/transporter-like factor in neural crest derived smooth muscle.
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PMID:Homocysteine signal cascade: production of phospholipids, activation of protein kinase C, and the induction of c-fos and c-myb in smooth muscle cells. 924 Sep 71

Bromocriptine (BC), an ergot alkaloid with wide therapeutic use in humans, has been shown to inhibit proliferation of several abnormally hyperproliferative cells in vivo and in vitro. In the present study, direct effects of BC on mitogen-stimulated proliferation of rat vascular smooth muscle cells (VSMC) (A7r5 cells) and human aortic smooth muscle cells (HAOSMC) were examined in vitro. Twenty-four hour proliferative responses of quiescent A7r5 cells and HAOSMC to a variety of mitogens in the presence or absence of BC were determined by quantifying the incorporation of 3H-thymidine into DNA. BC at 1 microM inhibited the responses of A7r5 cells to various concentrations of fetal calf serum (FCS) by 50-70% without affecting the ED50 of FCS (2%). BC dose dependently inhibited the proliferation of A7r5 cells and HAOSMC stimulated by 2% FCS, with 52% inhibition at 1 and 0.1 microM, respectively. BC at 1 microM also completely inhibited the maximal mitogenic responses of A7r5 cells to prolactin, platelet-derived growth factor, insulin-like growth factor, and phorbol mysterate acetate (PMA), and BC at 1 microM completely inhibited the mitogenic response of HAOSMC to PMA. BC is a dopamine D2 agonist, a noradrenergic alpha 2 agonist, and an .alpha 1 antagonist, but the inhibitory effects of BC on A7r5 cell proliferation could not be mimicked by the specific D2 agonists, LY162502 and LY171555; the alpha 2 agonist, clonidine; or the alpha 1 antagonist, WB-4101. Neither dopamine nor the D2 agonist, LY162502, could inhibit HAOSMC proliferation induced by FCS. The PMA-induced stimulation of protein kinase C (PKC), a positive regulator of mitogenesis, could be completely blocked in A7r5 cells and HAOSMC by 1 and 0.1 microM BC, respectively. However, FPCS (2%)-induced activation of PKC in A7r5 cells and HAOSMC could only be blocked by 61 and 19% by BC (1 microM for A7r5 cells and 0.1 microM for HAOSMC), respectively. Given the existing evidence that BC reduces the severity of several other pathological conditions, such as insulin resistance, inflammation, and hyperlipidemia, which potentiate vascular disease, the current findings further suggest that BC use in the treatment of atherosclerosis and/or restenosis deserves further investigation.
Atherosclerosis 1997 Aug
PMID:Inhibitory effects of bromocriptine on vascular smooth muscle cell proliferation. 925 5

Red blood cells (RBC) from patients with diabetes mellitus exhibit an increased propensity to adhere to cultured human umbilical vein endothelial cells (HUVEC) as a result of interaction of advanced glycation end products with their counter receptors, contributing to the pathogenesis of vascular complications. We determined whether the interaction of diabetic RBC with HUVEC induced cellular oxidant stress that would culminate in adherence and diapedesis of monocytes, these being initiating events in endothelial injury and atherogenesis. We show that the adherence of diabetic RBC (2% hematocrit), but not normal RBC, to HUVEC results in a fourfold increase in the production of lipid peroxides. Furthermore, diabetic RBC-induced oxidant stress causes a sixfold increase in platelet endothelial cell adhesion molecule-1 (PECAM-1) phosphorylation and doubles transendothelial migration of monocyte-like HL-60 cells; both are blocked by antioxidants and protein kinase C (PKC) inhibitors. Our results show that the adherence of diabetic RBC to endothelial cells initiates a cascade of cellular events resulting in PKC activation, causing PECAM-1 phosphorylation and concomitant transendothelial migration of monocytes. The increased diapedesis of monocytes, brought about by the interaction of diabetic RBC across vascular endothelium, may play an important role in accelerated atherosclerosis and cardiovascular disease in diabetics.
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PMID:Diabetic RBC-induced oxidant stress leads to transendothelial migration of monocyte-like HL-60 cells. 927 91

Reactive oxygen species (ROS) are believed to cause vascular injury in the pathophysiology of atherosclerosis, diabetes, and vasoocclusion in sickle cell disease. Studies have shown that ROS causes increased adhesion of monocytes and neutrophils to the endothelium. We investigated the effects of tert-butylhydroperoxide (t-BuOOH), an inducer of oxidant stress, to determine the cellular signaling pathway leading to the transendothelial migration of polymorphonuclear leukocytes. Our studies revealed that signaling by t-BuOOH in human umbilical vein endothelial cells (HUVECs) causes a twofold increase in the transendothelial migration of monocyte-like HL-60 cells and a fivefold increase in platelet endothelial cell adhesion molecule-1 (PECAM-1) phosphorylation. The transmigration induced by t-BuOOH was inhibited by an antibody to PECAM-1. These events were inhibited by antioxidants and inhibitors of protein kinase C, p21ras and glutathione synthesis. However, treatment of HUVECs with the phosphatase inhibitor calyculin A augmented the t-BuOOH-mediated transendothelial migration of monocytes and PECAM-1 phosphorylation. Our results suggest that oxidative stress can induce the transendothelial migration of monocytes as a result of phosphorylation of PECAM-1, a crucial event in the diapedesis of leukocytes during pathophysiology of vascular diseases.
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PMID:Oxidant stress-induced transendothelial migration of monocytes is linked to phosphorylation of PECAM-1. 931 33

Smooth muscle cell differentiation and proliferation are increasingly seen to be intimately tied to the etiology of atherosclerosis and hypertension. To determine the role of PKC alpha in the regulation of smooth muscle cell differentiation and proliferation, the rat embryonic smooth muscle cell line A7r5 was transfected with an expression vector containing the full-length PKC alpha cDNA. Neomycin-resistant clones which exhibited increased PKC alpha levels compared to wild-type cells were selected. The A7r5 cells overexpressing PKC alpha had altered morphology and decreased growth rates compared to wild-type cells and cells transfected only with the neomycin resistance gene. Electrophoretic mobility shift assays showed that nuclear extracts from overexpressing clones gave a different pattern of protein-DNA binding to an AP-1 consensus oligonucleotide compared to wild-type cells. In contrast to the growth characteristics of these clones, their levels of cell differentiation marker proteins such as vinculin and desmin were not affected by PKC alpha overexpression. Moreover, the smooth muscle-specific differentiation marker alpha-actin was markedly reduced, while beta-actin levels were found to remain unchanged. Northern blot analysis confirmed that alpha-actin downregulation occurred at the RNA level. Western blot analysis revealed that A7r5 cells have five different PKC isoforms and that these isoform protein levels were not changed by PKC alpha overexpression. These findings suggest that PKC alpha regulates growth and differentiation of A7r5 smooth muscle cells and that these changes might result from altered expression/function of AP-1 transcription factors.
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PMID:Effects of protein kinase C alpha overexpression on A7r5 smooth muscle cell proliferation and differentiation. 934 91

One of the responses of activated platelets to certain stimuli is the shedding of microparticles. Many studies have attempted to characterize the role of microparticles under various clinical situations or experimental conditions. Pathological levels of fluid shear stress may occur in diseased small arteries and arterioles partially obstructed by atherosclerosis or vasospasm and such shear stress may induce the activation and aggregation of circulating platelets. We investigated whether high shear stress could cause both platelet aggregation and shedding of microparticles from the platelet plasma membrane. A cone-plate viscometer was used to apply shear stress and microparticle formation was measured by flow cytometry. It was found that microparticle formation increased as the duration of shear stress increased. Both microparticles and remnant platelets showed procoagulant activity on their surfaces. Investigation of the mechanisms involved in shear-dependent microparticle generation showed that binding of von Willebrand factor to platelet glycoprotein Ib, influx of extracellular calcium, and activation of platelet calpain were required to generate microparticles under high shear stress conditions. Activation of protein kinase C promoted shear-dependent microparticle formation. These findings suggest that local generation of microparticles in atherosclerotic arteries, the site at which pathological levels of shear stress could occur, contributes to arterial thrombosis by providing and expanding a catalytic surface for the coagulation cascade.
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PMID:[Shear stress and platelet-derived microparticles]. 936 69

PD 166285, a novel protein tyrosine kinase inhibitor of a new structural class, the 6-aryl-pyrido[2,3-d]pyrimidines, was synthesized as the most potent and soluble analog of a series of small molecules originally identified by screening a compound library with assays that measured protein tyrosine kinase activity. PD 166285 was found to inhibit Src nonreceptor tyrosine kinase, fibroblast growth factor receptor-1, epidermal growth factor receptor and platelet-derived growth factor receptor beta subunit (PDGFR-beta), tyrosine kinases with half-maximal inhibitory potencies (IC50 values) of 8.4 +/- 2.3 nM (n = 6), 39.3 +/- 2.8 nM (n = 16), 87.5 +/- 13.7 nM (n = 6) and 98.3 +/- 7.9 nM (n = 16), respectively. PD 166285 also demonstrated inhibitory activity against mitogen-activated protein kinase (IC50 = 5 microM) and protein kinase C (IC50 = 22.7 microM). PD 166285 was further characterized as an ATP competitive inhibitor of Src nonreceptor tyrosine kinase, PDGFR-beta, fibroblast growth factor receptor-1 and epidermal growth factor receptor tyrosine kinases. In addition, PD 166285 inhibited PDGF- and EGF-stimulated receptor autophosphorylation in vascular smooth muscle cells (VSMCs) and A431 cells, respectively, and basic fibroblast growth factor-mediated tyrosine phosphorylation in Sf9 cells, with IC50 values of 6.5 nM, 1.6 microM and 97.3 nM, respectively, further establishing a tyrosine kinase mechanism of inhibition. The inhibition of PDGF receptor autophosphorylation in VSMCs by PD 166285 was long lasting and persisted for 4 days after a single 1-hr exposure followed by extensive washing. The PDGF-induced tyrosine phosphorylation of the 44- and 42-kDa mitogen-activated protein kinase isoforms was also blocked as a result of the inhibition of PDGF-stimulated receptor autophosphorylation by PD 166285 in VSMCs. The effects of PD 166285 were also demonstrated in functional assays of cell attachment, migration and proliferation, in which vascular cell adhesion to vitronectin, PDGF-directed chemotaxis and serum-stimulated cell growth were all potently inhibited with IC50 values of 80 yo 120 nM. Finally, PD 166285 uniquely demonstrated potent inhibition of phorbol ester-induced production of 92-kDa gelatinase A (MMP-9) in VSMC without affecting 72-kDa gelatinase B (MMP-2) as measured by gelatin zymography. These results highlight the biological characteristics of PD 166285 as a broadly active protein tyrosine kinase capable of potently inhibiting a number of kinase mediated cellular functions, including cell attachment, movement and replication. The potential therapeutic utility of this broadly acting inhibitor as an antiproliferative and antimigratory agent could extend to such diseases as cancer, atherosclerosis and restenosis, in which redundancies in protein kinase signaling pathways are known to exist.
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PMID:In vitro pharmacological characterization of PD 166285, a new nanomolar potent and broadly active protein tyrosine kinase inhibitor. 940 19


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