Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent data suggest that uric acid is generated locally in the vessel wall by the action of xanthine oxidase. This enzyme, activated during ischemia/reperfusion by proteolytic conversion of xanthine dehydrogenase, catalyzes the oxidation of xanthine, thereby generating free radicals and uric acid. Because of the potential role of ischemia/reperfusion in vascular disease, we studied the effects of uric acid on rat aortic vascular smooth muscle cell (VSMC) growth. Uric acid stimulated VSMC DNA synthesis, as measured by [3H]thymidine incorporation, in a concentration-dependent manner with half-maximal activity at 150 microM. Maximal induction of DNA synthesis by uric acid (250 microM) was approximately 70% of 10% calf serum and equal to 10 ng/ml platelet-derived growth factor (PDGF) AB or 20 ng/ml fibroblast growth factor. Neither uric acid precursors (xanthine and hypoxanthine) nor antioxidants (ascorbic acid, glutathione, and alpha-tocopherol) were mitogenic for VSMC. Uric acid was mitogenic for VSMC but not for fibroblasts or renal epithelial cells. The time course for uric acid stimulation of VSMC growth was slower than serum, suggesting induction of an autocrine growth mechanism. Exposure of quiescent VSMC to uric acid stimulated accumulation of PDGF A-chain mRNA (greater than 5-fold at 8 h) and secretion of PDGF-like material in conditioned medium (greater than 10-fold at 24 h). Uric acid-induced [3H]thymidine incorporation was markedly inhibited by incubation with anti-PDGF A-chain polyclonal antibodies. Thus uric acid stimulates VSMC growth via an autocrine mechanism involving PDGF A-chain. These findings suggest that generation of uric acid during ischemia/reperfusion contributes to atherogenesis and intimal proliferation following arterial injury.
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PMID:Uric acid stimulates vascular smooth muscle cell proliferation by increasing platelet-derived growth factor A-chain expression. 202 72

Neovascularization that generates collateral blood flow can limit the extent of tissue damage after acute ischemia caused by occlusion of the primary blood supply. The neovascular response stimulated by the BB homodimeric form of recombinant platelet-derived growth factor (PDGF-BB) was evaluated for its capacity to protect tissue from necrosis in a rat skin flap model of acutely induced ischemia. Complete survival of the tissue ensued, when the original nutritive blood supply was occluded, as early as 5 days after local PDGF-BB application, and the presence of a patent vasculature was evident compared to control flaps. To further evaluate the vascular regenerative response, PDGF-BB was injected into the muscle/connective tissue bed between the separated ends of a divided femoral artery in rats. A patent new vessel that functionally reconnected the ends of the divided artery within the original 3- to 4-mm gap was regenerated 3 weeks later in all PDGF-BB-treated limbs. In contrast, none of the paired control limbs, which received vehicle with an inactive variant of PDGF-BB, had vessel regrowth (P < 0.001). The absence of a sustained inflammatory response and granulation tissue suggests locally delivered PDGF-BB may directly stimulate the angiogenic phenotype in endothelial cells. These findings indicate that PDGF-BB can generate functional new blood vessels and nonsurgically anastomose severed vessels in vivo. This study supports the possibility of a therapeutic modality for the salvage of ischemic tissue through exogenous cytokine-induced vascular reconnection.
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PMID:Platelet-derived growth factor BB induces functional vascular anastomoses in vivo. 759 54

The influence of the somatostatin analogue angiopeptin on transplant arteriosclerosis was investigated using two aortic transplantation rat models. One was characterized by ischemia/reperfusion-induced changes in syngeneic transplants while immunologically induced changes dominated in the other allogeneic model. Angiopeptin, 100 micrograms/kg per day, was administered continuously until the sacrifice of the rats after 8 weeks. No additional immunosuppression was used in either model. An image analysis system was used to quantify the intimal and medial thicknesses of the grafts. In the syngeneic grafts, the intimal thickness was less than 50% of that of control grafts (P < 0.05), but no difference was seen in the allogeneic model. The expression of selected cells, TGF-beta s, and PDGF and PDGF alpha-receptors was detected immunohistochemically and displayed a similar picture in control and angiopeptin-treated grafts in both models. We conclude that angiopeptin has no clear immunosuppressive properties but may counteract ischemia-induced transplant arteriosclerosis.
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PMID:Effects of angiopeptin on transplant arteriosclerosis in the rat. 776 91

Abnormal smooth muscle cell (SMC) proliferation is observed in several pathological situations such as atherosclerosis, pulmonary hypertension, and venous pathologies, resulting in a thickening of the vessel wall. If endothelial cells have been assumed to play a role in the triggering of this proliferation, no direct evidence is available. As ischemia is often linked to these situations, we exposed human umbilical vein endothelial cells (HUVEC) to hypoxia. The HUVEC-conditioned medium was then added to SMC and the proliferation of these cells was measured. We observed a pro-proliferative activity for SMC of the hypoxic HUVEC-conditioned medium but not of the normoxic HUVEC one. This pro-proliferative activity could not be inhibited if HUVEC were treated with cycloheximide but was blocked if the synthesis of prostaglandins by HUVEC was inhibited during hypoxia. PGD2, and especially PGF2 alpha at the concentration found in the hypoxic HUVEC-conditioned medium, were demonstrated to have a mitogenic effect on SMC. PGE2 also showed a pro-proliferative activity but at higher concentrations. In addition, the kinetics of increase in SMC proliferation induced by a mixture of the four prostaglandins at the corresponding concentrations was the same as the one observed with hypoxic HUVEC-conditioned medium. However, when tested on fibroblasts which do not respond to PGF2 alpha, hypoxic HUVEC-conditioned medium also had a pro-proliferative activity. In addition, anti-bFGF antibodies but not anti-PDGF blocked the mitogenic activity of this conditioned medium for SMC. Finally, the mitogenic effects of PGF2 alpha and of bFGF on SMC are additive. These results indicate that bFGF is probably also involved. These results indicate that these prostaglandins act in synergy with bFGF and are the molecules responsible for the pro-proliferative activity observed in hypoxic HUVEC-conditioned medium. We propose that these findings can explain the excessive growth of SMC in blood vessels following chronic ischemic situations.
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PMID:Hypoxia stimulates human endothelial cells to release smooth muscle cell mitogens: role of prostaglandins and bFGF. 802 Jun 5

To elucidate the role of the platelet-derived growth factor (PDGF)-B chain in the brain, we examined its expression in rat brains with focal ischemia. Focal ischemia was induced by permanent tandem occlusion of the middle cerebral and common carotid arteries in spontaneously hypertensive rats (SHRs). Northern analysis demonstrated that ischemia transiently increased mRNA expression of the PDGF-B chain, but not the PDGF-A chain, in the injured neocortex. The larger transcript (3.5 kb) of the B chain gradually increased to threefold by 16 h, whereas the smaller transcript (2.6 kb) of the B chain markedly increased sixfold by 4 h. Immunohistochemistry revealed enhanced immunoreactivity in the neurons in the infarct and in the periinfarct area from 16 h to days 4-7, with a peak at 24 h. Furthermore, the brain macrophages that accumulated in the infarct showed intense immunostaining in their perinuclear region from days 2 to 14, with a peak at days 5-6. The present study demonstrates that ischemia induces the expression of the PDGF-B chain, first in neurons and later in brain macrophages, and suggests an important role of the PDGF-B chain in the healing process of the injured brain.
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PMID:Ischemia induces the expression of the platelet-derived growth factor-B chain in neurons and brain macrophages in vivo. 806 77

Present knowledge about cerebral limb ischemia has pointed out the importance of a versatile pharmacological approach, which considers not only the hydraulic aspect of the problem through a vasodilating action, but also all the hemorheologic and hemocoagulative implications, which seem to characterize the pathology itself. For about one year Trapidil has been entering the therapeutic treatments for arterio-vascular diseases in Italy; this drug was already known and tested abroad. Trapidil has shown a more complete antithrombocytic activity than other antiaggregating drugs; as a matter of fact it inhibits the formation of TXA2 through a mechanism of receptorial antagonism and at the same time it favours an increase of prostacyclina from the arterial walls. Moreover this drug is provided with a selective inhibition of the mitogenic effects of PDGF, which occurs for the block of the receptorial binding of this factor at the level of the myointimal cells. In conclusion, in some experimental models Trapidil seems to be able to improve the hemoreologic properties of the blood. Some different clinical studies have demonstrated the therapeutic effectiveness of Trapidil. In the treating of claudication and of the pain during the rest in AOCP, we want to report two studies which have shown a general improving either of the free interval of run or a reduction of the pain. In particular the polycentric study of Bonavita has examined 200 patients afflicted with AOCP at II and III stage, who were divided into three treatment groups: Trapidil, ticlopidina and picotamide.
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PMID:[Trapidil after one year]. 837 65

Locally produced cytokines and growth factors may mediate tissue remodelling processes, as observed in renal transplants exposed to ischemia or acute rejection episodes. The present study was designed to investigate mRNA transcript levels of platelet-derived growth factor (PDGF)-receptor beta, PDGF-A, PDGF-B, fibroblast growth factor-1, and transforming growth factor beta 1 in normal rat kidneys, in kidneys following contralateral nephrectomy and in renal transplants with acute or chronic rejection. Platelet-derived growth factor-receptor beta mRNA levels increased significantly in syngeneic and allogeneic transplants in the first week after transplantation and in allogeneic transplants with chronic rejection. Immunohistochemistry showed induction of PDGF-receptor beta protein expression on vascular wall cells in such grafts. Platelet-derived growth factor-A chain mRNA levels increased in day 3 allografts and in syngeneic LEW grafts, while PDGF-B chain mRNA levels showed no significant changes with transplantation. Fibroblast growth factor-1 mRNA levels were detectable in normal kidneys, tended to decrease with acute rejection, and increased significantly in chronic rejection. Transforming growth factor-beta 1 transcripts increased in acute and chronic rejection; immunohistochemistry showed predominantly glomerular localization of the transforming growth factor-beta 1 protein. We conclude that transplantation and rejection are associated with changes in the intragraft mRNA levels for several growth factors; chronic rejection is characterized by an increase in fibroblast growth factor-1 and transforming growth factor-beta 1 transcript levels.
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PMID:Growth factor transcripts in rat renal transplants. 880 45

Cytokines have been implicated as pivotal mediators of the wound-healing process. An understanding of the production and interaction of cytokines may lead to a better appreciation of the complex mechanisms of flap ischemia. The potential would then exist for novel diagnostic and therapeutic approaches to prevent and reverse damage to the endangered flap. The goal of this study was to determine the expression of parenchymal cytokines at various time points during flap ischemia. Punch biopsies were obtained from McFarlane dorsal flaps in the Sprague-Dawley murine model. We examined cytokine mRNA profiles for interleukin 1 alpha (IL-1 alpha), IL-2, IL-6, basic fibroblast growth factor (b-FGF), gamma-interferon (gamma IFN), transforming growth factor beta (TGF-beta), and platelet-derived growth factor A chain (PDGF-alpha) using in situ hybridization. Samples were taken from 0 to 48 hours postoperatively, with n = 3 for each time point. Eight hours postoperatively there was an abrupt peak of parenchymal cytokine expression at the bases of the flaps. Clinically at this time the flaps appeared completely viable without evidence of ischemic change. Leukocyte cytokine production peaked at 16 hours, when distal flap ischemia was evident clinically. These findings demonstrate an early peak of cytokine expression prior to clinical evidence of ischemia.
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PMID:Parenchymal cytokine expression precedes clinically observed ischemia in dorsal flaps in the rat. 882 26

The etiology of chronic rejection of kidney allografts is unknown, although hyperfiltration, acute rejection, viral infection and initial graft ischemia have been implicated. To test whether endothelial activation may be the link between these factors and chronic rejection, the endotoxin (lipopolysaccharide-LPS), a potent activator of endothelial cells, was evaluated in an established chronic rejection model. Bilaterally nephrectomized Lewis recipients of orthotopically transplanted Fisher 344 kidneys were treated briefly with low dose cyclosporine (1.5 mg/kg/day x 10). Recipients were given a non-lethal dose of LPS (2 mg) i.p. at 8 weeks and compared to allografted controls treated with vehicle. Urine protein was measured every 4 weeks. Rats in the treated group were sacrificed at 12 and 16 weeks, control animals at 12, 16 and 24 weeks (20/group) and examined histologically. In the chronically rejecting control allografts, progressive interstitial and glomerular sclerosis and vascular intimal proliferation had become apparent by 12 weeks. Infiltration of glomeruli, particularly by macrophages (M phi), and the coincident presence of cytokines were prominent, peaking at 16 weeks. LPS treatment accelerated and intensified these changes; proteinuria was more pronounced (16 weeks: 79 mg/24 h vs. 49 mg/24 h, p < 0.05). Numbers of infiltrating M phi peaked at 12 weeks in LPS treated hosts (69 c/FV vs. 27 c/FV in untreated controls, p < 0.01), accompanied by an increased upregulation of MHC class II and cytokine expression, particularly TNF alpha and PDGF around arteries and areas of infiltration. BY 16 weeks, 35 +/- 3% of glomeruli in LPS treated recipients had become sclerotic vs. 15 +/- 6% (p < 0.05) in controls, again associated with increased expression of cytokines (PDGF, TNF alpha, TGF beta), adhesion molecules (ICAM-1) and extracellular matrix proteins. Overall, the extent of chronic rejection of grafts in LPS treated rats at 16 weeks was similar to that developing in non-treated rats at 24 weeks. Activation of graft endothelium and/or host leucocytes increased the pace of graft infiltration and the expression of cytokines and other molecules. These events accelerate the process of chronic rejection.
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PMID:Infections and reduced functioning kidney mass induce chronic rejection in rat kidney allografts. 883 48

Our previous studies demonstrated coordinate expression of platelet-derived growth factor (PDGF) -B chain and beta-receptor in neurons at risk in the rat brain with focal ischemia. To clarify a role of the -B chain in the brain further, we examined whether PDGF-A or -B chain protects CA1 pyramidal neurons from delayed neuronal death after forebrain ischemia in rats. Pretreatment with PDGF-BB, but not -AA, at 120 ng/d for 2 days until forebrain ischemia was performed markedly ameliorated delayed neuronal death in CA1 pyramidal neurons on day 7 after ischemia. This neuroprotective effect of PDGF-BB was dose-dependent, and pretreatment with PDGF-BB at 240 ng/d showed almost complete inhibition of delayed neuronal death. In contrast, posttreatment with PDGF-BB at 120 ng/d starting 20 minutes after ischemia demonstrated no significant neuroprotective effect. The current study established marked neuroprotective actions of PDGF-BB in ischemic neuronal damage.
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PMID:Platelet-derived growth factor-BB, but not -AA, prevents delayed neuronal death after forebrain ischemia in rats. 934 35


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