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)

The three isoforms of transforming growth factor-beta (TGF-beta) have previously been implicated in embryonic development of the heart as well as in repair of myocardial damage after ischemia/reperfusion injury. TGF-beta 1 has also been localized intracellularly to both mitochondria and contractile filaments of cardiac myocytes, although its role in these structures has not been defined. We now report that exogenous TGF-beta stabilizes the beating rate of neonatal rat cardiac myocytes cultured on fibroblast matrix, and sustains their spontaneous rhythmic beating in serum-free medium. Moreover, using blocking antibodies to TGF-beta, we show that endogenous TGF-beta secreted by these myocytes acts in an autocrine fashion to maintain their beating rate. In contrast, IL-1 beta, an inflammatory mediator secreted by immune cells during myocardial injury, inhibits the beating of cardiac myocytes, and TGF-beta can overcome this inhibition. The antagonistic effects of TGF-beta and IL-1 were not observed when the myocytes were cultured on gelatin, as compared to native fibroblast matrix. The data indicate that TGF-beta is an important regulator of contractile function of the heart and have significant implications for understanding cardiac physiology in health and disease.
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PMID:Role of transforming growth factor-beta in maintenance of function of cultured neonatal cardiac myocytes. Autocrine action and reversal of damaging effects of interleukin-1. 143 Feb 28

We studied the effects of transforming growth factor-beta (TGF-beta), tissue plasminogen activator (tPA), and their combination in cats subjected to splanchnic artery occlusion (SAO) with reperfusion. Untreated anesthetized cats subjected to total occlusion of the celiac, superior, and inferior mesenteric arteries for 120 min, followed by reperfusion, uniformly died within 120 min after reperfusion. The mean survival time was 75 +/- 8 min. Plasma amino-nitrogen concentrations and cathepsin D and myocardial depressant factor (MDF) activities were markedly elevated following reperfusion. Superior mesenteric artery (SMA) rings isolated from cats subjected to SAO with reperfusion exhibited a significant loss of vasorelaxation to the endothelium-dependent dilators acetylcholine and A-23187. Administration of tPA (1 mg/kg) intravenously just before reperfusion did not prolong survival time (81 +/- 10 min) nor did it influence any biochemical or cardiovascular responses following reperfusion or ameliorate the depressed endothelium-dependent relaxation of SMA rings. In contrast, TGF-beta (50 micrograms/cat) ameliorated the SAO postreperfusion state in terms of survival rate and plasma MDF activity, and protected against depressed endothelium-dependent relaxation of SMA rings. TGF-beta alone slightly increased the survival time to 102 +/- 11 min. However, combined treatment with tPA (1 mg/kg) and TGF-beta (50 micrograms/cat) preserved endothelium-dependent relaxation and prevented increases in plasma amino-nitrogen more prominently than TGF-beta given alone and significantly increased the survival time to 118 +/- 3 min (p less than 0.01). These results indicate that TGF-beta exerts beneficial effects in SAO followed by reperfusion in cats, and tPA has an augmenting action on some of the beneficial effects of TGF-beta. These findings suggest that TGF-beta alone or in combination with tPA may be potentially useful therapeutic regimens in splanchnic ischemia shock by preserving splanchnic parenchymal and endothelial cells.
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PMID:Beneficial effects of transforming growth factor-beta and tissue plasminogen activator in splanchnic artery occlusion and reperfusion in cats. 171 97

Transforming growth factors beta are multifunctional proteins and regulators of cell proliferation and differentiation. Transforming growth factor-beta s have the capacity to rescue adult neurons from ischemia- and glutamate-induced cell death and are prominent in the embryonic and adult brain including striatum and substantia nigra. In the present study we show that transforming growth factors-beta 1, -2, and -3 promote, in a dose-dependent fashion, in vitro survival of tyrosine hydroxylase-immunoreactive dopaminergic neurons isolated from the embryonic rat mesencephalon floor. The magnitude of the effect, which was half-maximal at a concentration of 20 pM, was identical for all three transforming growth factor-isoforms and matched that of fibroblast growth factor-2. Unlike fibroblast growth factor-2, however, transforming growth factor-beta s did not increase numbers of astroglial cells visualized by using antibodies to glial fibrillary acidic protein, and had no effect on cell proliferation monitored by incorporation of BrdUrd. Transforming growth factor-beta s were significantly more potent than fibroblast growth factor-2 in protecting dopaminergic neurons against N-methyl-4-phenylpyridinium ion toxicity. RT-PCR analysis indicated that the effect of transforming growth factor-beta s is not mediated by glial cell-derived neurotrophic factor, which was not detectable in cultures at various time points. On the other hand transforming growth factor-beta 2 mRNA could be detected in freshly isolated and cultured mesencephalic cells, and its immunoreactivity has also been demonstrated in the embryonic day 14 mesencephalon floor. We conclude that transforming growth factor-beta has trophic and protective effects on developing dopaminergic neurons.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Transforming growth factor-beta promotes survival of midbrain dopaminergic neurons and protects them against N-methyl-4-phenylpyridinium ion toxicity. 770 May 16

Although transforming growth factor-beta s (TGF-beta s) are expressed widely in both adult and embryonic rat heart, both mRNA and protein expression increase following ischemic injury. Furthermore, exogenous administration of TGF-beta decreases cardiac damage following ischemia-reperfusion in rats. We have found that treatment of primary cultures of neonatal rat cardiomyocytes or cardiac fibroblasts with TGF-beta 1, 2, or 3 results in increased expression of TGF-beta 1, 2, and 3 mRNA. TGF-beta 2 was generally the least effective isoform in inducing TGF-beta expression. In cardiac fibroblasts mRNA expression of all TGF-beta s increased 2-3-fold following 1 h of treatment and decreased to control levels by 8 h which was accompanied by a 2.5- and 2.3-fold increase in TGF-beta 1 and 2 protein secretion, respectively. By 48 h of treatment mRNA levels for TGF-beta s 2 and 3 were less than 10% of control levels. In cardiomyocytes two-five-fold increases in mRNA levels were observed following 1-24 h of TGF-beta 1 treatment, but TGF-beta 1 and 3 mRNA levels returned to control values by 48 h while TGF-beta 2 mRNA expression remained elevated. TGF-beta 1 and 2 protein secreted by the cardiac myocytes was increased 2.9- and 1.7-fold, respectively. Autoinduction of TGF-beta s may play a beneficial role in cardiac wound healing by sustaining transient increases in TGF-beta levels from either endogenous synthesis or exogenous application.
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PMID:Autoinduction of mRNA and protein expression for transforming growth factor-beta S in cultured cardiac cells. 777 87

Previous studies have demonstrated that transforming growth factor-beta (TGF-beta) can accelerate wound healing, inhibit free radical formation and limit myocardial ischemia/reperfusion injury in a variety of experimental models. However, it is unknown whether exogenous TGF-beta 1 can attenuate the prolonged contractile dysfunction that is observed after a brief, reversible ischemic insult (myocardial stunning). Thus, open-chest dogs undergoing a 15-min left anterior descending coronary artery occlusion and 4 h of reperfusion were given TGF-beta 1 as an intravenous bolus (250 micrograms) at 24 h and again at 1 h before coronary occlusion (n = 5). Control dogs (n = 7) received equivalent amounts of vehicle. The two groups were similar with respect to occluded bed size, collateral blood flow and rate-pressure product. Fundamental physiological parameters, such as body temperature, arterial pH, PO2 and hematocrit, were within normal limits throughout the experiment. In control dogs, regional myocardial function (assessed as systolic thickening fraction) remained depressed throughout the 4 h reperfusion period, indicating severe myocardial stunning. TGF-beta 1 did not produce any significant improvement in the recovery of regional function; 4 h after reperfusion, paradoxical systolic thinning was still present in both treated and control groups, with thickening fraction being -22.5 +/- 6.1% and -31.0 +/- 5.3% of baseline, respectively (P = N.S.). These results demonstrate that a large dose of TGF-beta 1 given before ischemia fails to attenuate myocardial stunning in the open-chest dog, suggesting that this growth factor does not exert protective effects in the setting of reversible myocardial ischemia/reperfusion injury.
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PMID:Effect of transforming growth factor-beta 1 on myocardial stunning in the intact dog. 834 Sep 31

We observed previously that 20 min of global cerebral ischemia followed by 45 min of reperfusion selectively blocked cerebral vasodilation to hypercapnia and hypotension. This study determines the effects of pretreatment with transforming growth factor-beta (TGF-beta) on cerebrovascular responses after cerebral ischemia in piglets equipped with closed cranial windows. Hypercapnia-induced pial arteriolar dilation was blocked after cerebral ischemia (20 +/- 1 vs. 2 +/- 1% dilation before and after ischemia, respectively). Similarly, the increases in periarachnoid cortical cerebrospinal fluid 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) and prostaglandin E2 (PGE2) concentration in response to hypercapnia were blocked (2.5 +/- 0.2- vs. 0.2 +/- 0.4-fold and 2.1 +/- 0.1- vs. 0.3 +/- 0.4-fold increase in 6-keto-PGF1 alpha and PGE2, respectively). Treatment with topical TGF-beta (400 ng/ml) before and during ischemia-reperfusion attenuated the loss of hypercapnia-induced cerebrovascular dilation (20 +/- 1 vs. 14 +/- 1% dilation before and after ischemia, respectively) and the loss of associated changes in cerebrospinal fluid prostanoids (2.0 +/- 0.2- vs. 1.7 +/- 0.2-fold and 2.3 +/- 0.2- vs. 2.2 +/- 0.3-fold increase in 6-keto-PGF1 alpha and PGE2 before and after ischemia, respectively). The loss of cerebrovascular dilation in response to hemorrhagic hypotension after ischemia was similarly prevented by TGF-beta. Cerebrovascular dilation to topical isoproterenol was unchanged after ischemia. TGF-beta may preserve endothelial cell function. We conclude that topical TGF-beta can attenuate cerebromicrovascular compromise caused by ischemia-reperfusion in newborn pigs.
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PMID:Transforming growth factor-beta attenuates ischemia-induced alterations in cerebrovascular responses. 844 54

Endothelial dysfunction is an important early-recurring phenomenon in virtually all forms of ischemia-reperfusion, including a variety of circulatory shock states. The dysfunction appears to be triggered within 2.5 min of the endothelial generation of a large burst of superoxide radicals. However, the initial dysfunction may be amplified by neutrophil-generated factors including oxygen-derived free radicals, cytokines, proteases, and lipid mediators. Moreover, adhesive molecules on the surface of the PMN, along with their ligands on the endothelial cell membrane, appear to promote endothelial dysfunction in ways that may go beyond the adherence of neutrophils on the endothelial surface. These interactions remain to be elucidated but may involve intricate cell signaling pathways. A variety of pharmacologic agents exert endothelial protective effects in ischemia-reperfusion and circulatory shock states. Table 1 summarizes these agents and indicates the major mechanism of preservation of the endothelium. These substances can be classified into three broad categories: (a) substances replacing endogenous cytoprotective agents of endothelial origin including prostacyclin (PGI2), endothelium-derived relaxing factor (EDRF), and adenosine: the endothelium protecting agents include these substances as well as stable analogs of PGI2, and nitric oxide donors; (b) substances that inhibit pro-inflammatory mediators of endothelial origin: the pro-inflammatory agents are primarily platelet activating factor (PAF) and oxygen-derived free radicals (e.g. superoxide radicals) although other mediators may be involved. The therapeutic agents useful in this area are PAF receptor antagonists and free radical scavengers (e.g. superoxide dismutase); (c) substances that inhibit neutrophils or neutrophil-derived mediators: the major neutrophil-derived mediators are oxygen-derived free radicals, cytokines (e.g. TNF alpha and IL-1 beta), proteases (e.g. elastase), and lipid mediators (e.g. LTB4). In addition, adhesive molecules on the neutrophil surface and their endothelial ligands promote endothelial dysfunction and the action of adherent neutrophils. Agents that inhibit some of these mediators are transforming growth factor-beta (TGF-beta), elastase inhibitors, leukotriene B4 (LTB4) receptor antagonists and monoclonal antibodies to adhesive proteins (e.g. anti-CD18, anti-ICAM-1). Further work is needed to clarify these findings and to determine the physiologic and pathophysiologic interactions among these diverse agents. This topic of endothelial dysfunction represents a fertile area for further investigation to elucidate the complex mechanisms of neutrophil-endothelial interactions. These interactions lead to neutrophil adherence to the endothelium, neutrophil migration into the underlying tissues, and subsequent tissue injury (e.g. myocardial reperfusion injury).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pharmacology of the endothelium in ischemia-reperfusion and circulatory shock. 849 55

Effective mechanisms of laser photocoagulation for neovascularization in diabetic retinopathy were investigated in regard to change in oxygen pressure in the retina and vitreous and cytokines related to ischemia. The mechanism of laser photocoagulation is suggested to be as follows. 1. Destruction of the outer retina, especially of photoreceptors that have high oxygen consumption decreases metabolic function of the outer retina and its oxygen consumption. 2. The destruction allows increase of oxygen diffusion from choroidal vessels to inner retina, which improves the metabolic function by equilibrating oxygen demand and supply in the inner retina. (3) Production and secretion of neovascular factors such as vascular endothelial growth factor (VEGF) is decreased by the improvement of hypoxia. 4. The neovascularization is decreased by the synergistic effect between the neovascular factors and suppressors such an VEGF, fibroblast growth factor (FGF), and transforming growth factor-beta (TGF-beta). The improvement of the retinal ischemia and the decrease of cytokines are implicated in the regression of neovascularization by the laser photocoagulation for diabetic retinopathy.
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PMID:[Effective mechanisms of laser photocoagulation for neovascularization in diabetic retinopathy]. 865 Oct 51

Although transforming growth factor-beta (TGF-beta) is known to be multifunctional in many physiological systems, its role in the brain is undergoing elucidation. The situation is made more complex by the presence of multiple isoforms, which may be differentially regulated and have various activities in each particular cell type. Because neurons are dependent on neurotrophic factors for survival, we utilized a rat model of transient forebrain ischemia (TFI) to test the hypothesis that TGF-beta isoforms are important in the hippocampal response to injury. Northern blot analysis demonstrated a differential and temporal alteration in TGF-beta isoform expression following TFI. In-situ hybridization experiments revealed that at day 1 following TFI, there was a strong neuronal increase in the TGF beta-1 transcript but a reciprocal decrease in TGF-beta 2 and -beta 3 transcript levels. Immunohistochemical analysis of all three TGF-beta s demonstrated at day 1 following TFI a loss of the immunoreactive proteins in the vulnerable CA-1 hippocampal neurons, but protein preservation in the CA-2-4 neurons which are more resistant to the ischemic insult. At 3-5 days following TFI, significant extraneuronal changes in TGF-beta isoform expression were also detected. Double-staining experiments with antibody to glial fibrillary acidic protein (GFAP) as a marker for astrocytes, and lectin isolectin B4 Griffonia simplicifolia for microglia, demonstrated increased expression of all TGF-beta isoforms in astrocytes but not microglia. Taken together, these results suggest that the TGF-beta peptides in neurons and astrocytes are important endogenous mediators in the CNS response to ischemic injury.
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PMID:Differential neuronal and astrocytic expression of transforming growth factor beta isoforms in rat hippocampus following transient forebrain ischemia. 884 7

Peptide growth factors have been reported to contribute to the atherogenic process, and they are known to mediate signals for vascular remodeling. Using syngeneic and allogeneic rat aorta transplant models, we analyzed the impact of cold ischemia time up to 24 hours and reperfusion injury on development of transplant arteriosclerosis during the first 2 months after transplantation. The expression of the transforming growth factor-beta (TGF-beta) family as well as the platelet-derived growth factor (PDGF) and its receptors was studied by use of immunohistochemistry, followed by semiquantitative evaluation and multivariate analysis. In the syngeneically transplanted aortas, the expression of TGF-beta 1, PDGF, and the two PDGF receptors in the neointima increased significantly with the extent of cold ischemia time. Furthermore, there was a significant induction of the latent TGF-beta binding protein in the neointima as well as TGF-beta 2 in the media, both correlating with the observation time after transplantation. In the allogeneic grafts, all examined proteins were already induced strongly 2 weeks after transplantation, even at the shortest ischemic period studied (1 hour). However, no positive correlation between growth factor expression and cold ischemia or observation time could be found. Double immunohistochemistry revealed that macrophages express PDGF and its receptors as well as TGF-beta 1. Smooth muscle cells express both types of PDGF receptors, and a few T cells express TGF-beta 1 as well as PDGF receptors. In summary, TGF-beta and PDGF are induced by allogeneic as well as ischemic stimuli in transplanted aortas, suggesting a role in the pathogenesis of transplant arteriosclerosis and representing a potential target for therapeutic intervention.
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PMID:Ischemia-induced transplant arteriosclerosis in the rat. Induction of peptide growth factor expression. 897 57


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