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)

A rapid growth of the coronary vasculature occurs during prenatal and early postnatal periods as precursor cells from the epi- and sub-epicardium differentiate, migrate and form vascular structures (vasculogenesis) which then fuse, branch and in some cases recruit cells to form three tunics (angiogenesis). These processes are tightly controlled by temporally and spatially expressed growth factors which are stimulated by metabolic and mechanical factors. The process of angiogenesis in the myocardium is not limited to developmental periods of life, but may occur when the heart is challenged by enhanced loading conditions or during hypoxia or ischemia. This review focuses on the activation of growth factors by metabolic and mechanical stimuli in the developing heart and in the adult heart undergoing adaptive responses. Experimental studies support the hypotheses that both metabolic (hypoxia) and mechanical (stretch) factors serve as powerful stimuli for the up-regulation of growth factors which facilitate angiogenesis and arteriogenesis. Both hypoxia and stretch are powerful inducers of VEGF and its receptors, and provide for paracrine and autocrine signaling. In addition to the VEGF family, bFGF and angiopoietins play major roles in myocardial vascularization. Sufficient evidence supports the hypothesis that mechanical (e.g., bradycardia) and metabolic (e.g., thyroxine analogs) may provide effective non-invasive angiogenic therapies for the ischemic and post-infarcted heart.
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PMID:Growth factor activation in myocardial vascularization: therapeutic implications. 1554 30

Severe acute renal failure (ARF) remains a common, largely treatment-resistant clinical problem with disturbingly high mortality rates. Therefore, we tested whether administration of multipotent mesenchymal stem cells (MSC) to anesthetized rats with ischemia-reperfusion-induced ARF (40-min bilateral renal pedicle clamping) could improve the outcome through amelioration of inflammatory, vascular, and apoptotic/necrotic manifestations of ischemic kidney injury. Accordingly, intracarotid administration of MSC (approximately 10(6)/animal) either immediately or 24 h after renal ischemia resulted in significantly improved renal function, higher proliferative and lower apoptotic indexes, as well as lower renal injury and unchanged leukocyte infiltration scores. Such renoprotection was not obtained with syngeneic fibroblasts. Using in vivo two-photon laser confocal microscopy, fluorescence-labeled MSC were detected early after injection in glomeruli, and low numbers attached at microvasculature sites. However, within 3 days of administration, none of the administered MSC had differentiated into a tubular or endothelial cell phenotype. At 24 h after injury, expression of proinflammatory cytokines IL-1beta, TNF-alpha, IFN-gamma, and inducible nitric oxide synthase was significantly reduced and that of anti-inflammatory IL-10 and bFGF, TGF-alpha, and Bcl-2 was highly upregulated in treated kidneys. We conclude that the early, highly significant renoprotection obtained with MSC is of considerable therapeutic promise for the cell-based management of clinical ARF. The beneficial effects of MSC are primarily mediated via complex paracrine actions and not by their differentiation into target cells, which, as such, appears to be a more protracted response that may become important in late-stage organ repair.
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PMID:Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. 1595 79

To test the hypothesis that overexpression of early growth response factor-1 (Egr-1) contributes to the revascularization of ischemic limbs, a constitutively active form of Egr-1 (Egr-1*) was made and evaluated in vitro and in vivo. Analyses of the transduced myocytes revealed significant upregulation of bFGF, PDGF-A, PDGF-B, IGF-II, and TGF-beta1. A coculture assay of the paracrine effects indicated that Ad-Egr-1* promoted proliferation and migration of endothelial cells. When Ad-Egr-1* was injected into the tibialis anterior muscle of mice, followed by explant culture in growth factor-reduced Matrigel, many capillary-like structures were observed in the Egr-1* group compared with minimal sprouting from the LacZ group, suggesting an angiogenic potential of Egr-1*. Next we evaluated Ad-Egr-1* in a murine model of hindlimb ischemia. Compared with slow revascularization in the control PBS or LacZ group, a rapid increase in tissue perfusion was observed in the Egr-1* group and the difference in flux ratio was statistically significant at day 7. In the injected muscle, expression of Egr-1*, upregulation of its target genes, and increased number of vessels staining positive for smooth muscle alpha-actin were observed. These results suggest that Egr-1 plays an important role in vascular recovery after occlusion and could be a potential target for therapeutic angiogenesis.
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PMID:Adenoviral-mediated delivery of early growth response factor-1 gene increases tissue perfusion in a murine model of hindlimb ischemia. 1604 1

The pathogenesis of skin scleroderma (LS) is still unknown. Disturbances of vessels system, connective tissue metabolism and humoral and cellular immunological response is observed. Antinuclear antibodies are detected in 30-80% of patients with different types of skin scleroderma. They are present more often in patients with disseminated lesions and linear type of LS compared to morphoea au plaque. In our own analysis 28.5% of patients had also antibodies directed against Borrelia burgdorferi. It is believed that the injury of endothelial cells and proliferation in medial part of small vessels - which both lead to chronic ischemia - are the earliest disturbances observed in histopathological examination of the skin taken from systemic as well as from skin scleroderma patients. During last few years, there were some interesting reports concerning functional changes of endothelial cells which led to disturbances in tension of vessels smooth muscles. Free radicals - in genetically predispose people--can also provoke scleroderma lesions through their injury action on endothelial cells and stimulation of fibroblasts. In morphoea, the process of fibrosis begins around vessels. Deposition of connective tissue matrix is observed, especially collagen type I and III. This stimulation of fibroblasts as well as accumulation of connective tissue matrix are secondary to some stimulatory factors. These are: PDF, bFGF, TGFbeta and some cytokines. In morphoea patients serum levels of IL-1, IL-2, IL-4, IL-6 and IL-8 were elevated. In literature, levels and production of collagenases were decreased, although more authors say that tissue inhibitors of metalloproteinases are the main factor in fibrosis. The analysis of data tends to suspicion that enormous fibrosis observed in different types of scleroderma can be the result of increased production of collagen and other components of connective tissue as well as their incomplete degradation. Presented clinical and laboratory data show how many different factors influence etiopathogenesis of morphoea.
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PMID:[Pathogenesis of skin scleroderma--literature review]. 1633 38

Clinical trials of therapeutic angiogenesis for the treatment of cardiovascular ischemia have failed to meet the expectations with the use of single growth factors, namely VEGF and bFGF. We show here that a bovine bone-derived growth factor mixture (GFM) of TGFbetas, BMPs, and no more than 0.1% aFGF can initiate a dose-dependent angiogenic response in subcutaneously implanted Growth Factor Reduced Matrigel plugs that includes abundant smooth muscle actin positive (SMA+) tubes and functional CD31+, red blood cell filled, capillaries. Tube forming activity of the single factors, recombinant bFGF and bone-derived TGF-beta2, were comparable to GFM, but only the bone-derived factors were able to create a larger fraction of SMA+ tubes than Matrigel alone at an equal dose. Basic FGF formed a greater number of RBC-filled capillaries within the plugs than GFM or TGF-beta2 at the highest doses, although GFM created RBC-filled capillaries that penetrated deeper into the plugs than bFGF. However, bFGF showed the greatest number of non-cell-lined, RBC-filled pools, suggestive of vessel rupture, and the largest number of plugs showing signs of fluid accumulation in the form of large, cell-lined clefts in the implants. TGF-beta2 showed less RBC-filled pools, but a significant number of implants with signs of fluid accumulation. At high doses of GFM penetration by blood vessels and mesenchymal cells was obstructed by cartilage development within the plugs accompanied by a prominent band of SMA+ granulation tissue with abundant RBC-filled capillaries encapsulating the implants. Thus, GFM is also capable of dramatically remodeling the vascular system in the interstitial space surrounding the plug. These results show that GFM is capable of inducing the formation of a more mature vascular system than that formed by the single factors bFGF and TGFbeta-2. Natural mixtures of TGFbetas, BMPs, and FGFs may have superior clinical utility in therapeutic angiogenesis applications.
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PMID:A bone-derived mixture of TGF beta-superfamily members forms a more mature vascular network than bFGF or TGF-beta 2 in vivo. 1640 May 22

Much effort has been made in searching for multipotent cell types with high therapeutic potentials for repair of damaged tissue. Through enzymatic digestion of fat tissue, it is possible to obtain a large number of stromal cells. Isolated cells show a high proliferate capacity in culture. All this makes adipose stromal cells (ASC) promising candidates for their use in cell therapy. This review is focused on analyzing the surface antigen profile of isolated population of ASC, expression of angiogenic factors by these cells, as well as on their differentiation potential. A high percentage of ASC population initially express the progenitor cell marker CD34, but during culturing, cells exhibit a mesenchymal cell phenotype and express CD29, CD105, CD106, CD166. Culturing ASC in specific differentiation media induces expression of early markers of differentiated mesenchymal cells, such as adipocytes, chondrocytes and osteoblasts, as well as myoblasts, cardiomyocytes and neural cells. It has been also shown that ASC have a strong pro-angiogenic potential, they are able to secret growth factors, such as VEGF, HGF, bFGF and others, which stimulate survival and proliferation of endothelial cells. In addition, systemic or local delivery of ASC to mice with hindlimb ischemia stimulates recovery of injured tissue and blood flow. Potential clinical uses of ASCs are discussed in the review.
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PMID:[Adipose stromal cells--plastic type of cells with high therapeutic potential]. 1673 75

The study aims to explore the protection mechanism of exogenous basic fibroblast growth factor (exo-bFGF) in brain ischemia. The first part of experiment was to determine the optimal time window for the permeation of exo-bFGF through damaged blood-brain barrier in rats with permanently occluded middle cerebral arteries. 125I labeled bFGF was administered to the rats through the caudal vein. The level of gamma-rays of 125I-bFGF in the ischemic brain were found to increase at 2 h and a high level was maintained for 14 days. The morphology of the basement membrane of capillaries was observed using anti-blood-brain barrier basement membrane glycoprotein immunohistochemistry. The normal continuous linear or ribbon-like immunostain of the basement membrane became granular at 0.5 h, gradually faint and finally negative. The newly formed capillaries at the edge of the infarct still showed a negative stain after 14 days. The result suggested the optimal time window of exo-bFGF began 2 h after insult. The second part of experiment was to observe the dynamic expression of early growth response protein (Egr-1), endogenous basic fibroblast growth factor (endo-bFGF) and bFGF receptor (bFGFR) using immunohistochemistry after exo-bFGF is administered to brain. Egr-1 was more significantly enhanced in the exo-bFGF-used group than in the control group. Endo-bFGF increased gradually, reaching its peak at 7 days in the control group, while in experiment group, the endo-bFGF expression showed its first peak at 6 h, indicating that exo-bFGF could induce earlier and stronger expression of endo-bFGF. The bFGFR-group presented an early expression, reaching its maximal level at 3 h, and declining at 6 h. There were no difference in expression of bFGFR between the two groups. The infarct areas reduced from 17% to 24% in the different time intervals. The results suggested that in exo-bFGF enhanced Egr-1 protein. Egr-1 in turn might play an important role in up-regulating the expression of endo-bFGF which overlapped with the expression of bFGFR to ensure the combination of ligand and receptor to protect against brain ischemia.
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PMID:Permeability of injured blood brain barrier for exogenous bFGF and protection mechanism of bFGF in rat brain ischemia. 1677 Nov 84

The successful use of tissue-engineered transplants is hampered by the need for vascularization. Recent advances have made possible the using of stem cells as cell sources for therapeutic angiogenesis, including the vascularization of engineered tissue grafts. The goal of this study was to examine the endothelial potential of human umbilical cord-derived stem (UCDS) cells. UCDS cells were initially characterized and differentiated in an endothelial differentiation medium containing VEGF and bFGF. Differentiation into endothelial cells was determined by acetylated low-density lipoprotein incorporation and expression of endothelial-specific proteins, such as PECAM and CD34. In vivo, the transplanted UCDS cells were sprouting from local injection and differentiated into endothelial cells in a hindlimb ischemia mouse model. These findings indicate the presence of a cell population within the human umbilical cord that exhibits characteristics of endothelial progenitor cells. Therefore, human umbilical cord might represent a source of stem cells useful for therapeutic angiogenesis and re-endothelialization of engineered tissue grafts.
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PMID:In vitro and in vivo differentiation of human umbilical cord derived stem cells into endothelial cells. 1696 Aug 77

Recombinant adeno-associated virus (rAAV)-based gene therapy represents a promising approach for the treatment of heart diseases. It has been shown that growth hormone (GH) exerts a favorable effect on cardiovascular function in clinical and animal studies. This study explores a chronic stage after myocardial infarction and the potential therapeutic effects of delivering a human GH gene by rAAV following coronary artery ligation in Sprague-Dawley rats. rAAV vectors stably transduced heart muscle for up to 22 weeks after myocardial infarction (MI). Overexpression of GH via rAAV vectors significantly improved not only cardiac function but also LV pathologic remodeling was attenuated post-MI compared to the control rAAV-lacZ injected group. rAAV-mediated expression of GH also resulted in a significant induction of several angiogenic genes such as eNOS, VEGF and bFGF in rat hearts. Immunohistochemistry revealed an increase in capillary density and proliferation of cells and a decrease in the number of TUNEL-positive cardiomyocytes in the rAAV-GH group. Based on these data, we conclude that rAAV-mediated GH delivery can render a long-term transduction in the infarcted heart and improve cardiac function through promoting angiogenesis and proliferation of cells and protecting cardiomyocytes from ischemia-induced apoptosis.
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PMID:Long-term stable expression of human growth hormone by rAAV promotes myocardial protection post-myocardial infarction. 1717 22

Stress is a major etiologic factor in the pathogenesis of gastric and duodenal ulceration, as first described in rats by Hans Selye. In patients with "peptic ulcers" duodenal ulcers are more frequent than gastric ulcers (except in Japan). Thus, our research during the last three decades focused on the molecular mechanisms of duodenal ulcer in rodent models of chemically induced duodenal ulceration, and here we review our three recent findings: Endothelins (ET-1), the immediate early gene egr-1 and imbalance of angiogenic/antiangiogenic molecules. Namely, we found an enhanced expression and release of ET-1 within 15-30 min after the administration of duodenal ulcerogen cysteamine, resulting in local ischemia that triggers the expression of hypoxia-inducible factors (HIF-1alpha). Our gene expression studies also revealed an early (0.5-2 h) increase in the expression of egr-1 that is followed (12-24 h) by upregulation of angiogenic growth factors (e.g., VEGF, bFGF, PDGF). Surprisingly, this event is also associated with an enhanced production of angiostatin and endostatin that probably counteract the beneficial effect of angiogenic molecules. Thus, the initial injury to endothelial and epithelial cells in duodenal ulceration seems to be aggravated (and not initiated) by HCl and proteolytic enzymes. The resulting mucosal necrosis does not rapidly heal because of the imbalance of VEGF and angiostatin/endostatin, hence duodenal ulcers develop. The experimental ulcers Selye described morphologically are now characterized at the molecular and genome level, involving unexpected mediators like ET-1, egr-1 and angiogenesis-related molecules.
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PMID:New molecular mechanisms of duodenal ulceration. 1765 71


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