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 most effective way to augment neural progenitor proliferation after ischemia is still unknown. We administered various agents into the rat cerebral ventricle after transient global ischemia and compared the neural progenitor response in the anterior subventricular zone (aSVZ), dentate gyrus subgranular zone, posterior periventricle, and hypothalamus. We demonstrated that cocktail administration of epidermal growth factor (EGF) and fibroblast growth factor-2 (FGF-2) remarkably increased the numbers of neural progenitors in all four regions examined. The addition of Notch ligand DLL4 to the cocktail elicited the largest progenitor response in the aSVZ and hypothalamus. Our results suggest that EGF and FGF-2, combined with DLL4, represent the universally applicable regimen for the expansion of the neural progenitor pool following ischemia.
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PMID:Region-specific proliferative response of neural progenitors to exogenous stimulation by growth factors following ischemia. 1846 91

Intercellular signaling via cell-surface Notch receptors controls the cell-fate decision in the developing brain. Recent studies have suggested that the response of endogenous neural stem cells to brain injury in adult mammals might be mediated by Notch signaling. Here, we investigated the role of Notch signaling in ischemic damage in the hippocampal CA1 region after transient global ischemia in rats. In the acute phase of ischemia, Notch1-positive cells increased in number in the posterior periventricle, which is the posterior part of the lateral ventricle, after the i.c.v. administration of epidermal growth factor and fibroblast growth factor-2. In addition, Notch signaling was upregulated in the CA1 region 5 days after ischemia. By contrast, the attenuation of Notch signaling caused by the administration of a gamma-secretase inhibitor in the subacute phase (6-12 days after ischemia) amplified the immature migratory neurons 12 days after ischemia, and resulted in an increased number of newly generated neurons in the CA1 after 28 days. Our results suggest that Notch signaling in the CA1 is activated in parallel with the increase of endogenous neural stem cells stimulated by ischemia, and that the attenuation of Notch signaling could induce more efficient differentiation of neural progenitors toward a neuronal lineage.
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PMID:Attenuation of Notch signaling promotes the differentiation of neural progenitors into neurons in the hippocampal CA1 region after ischemic injury. 1901 38

ErbB receptor tyrosine kinases are important in maintaining the long-term structural integrity of the heart and in the induction of hypertrophy. In addition, in vivo activation of ErbB1 by epidermal growth factor (EGF) protects the heart against acute stress-induced damage. We examined here whether the ErbB sytem acutely protects the isolated heart in which stress was induced in vitro by ischemia combined with epinephrine infusion (EPI). In perfused mouse hearts, EGF induced Tyr-phosphorylation of ErbB1 but not ErbB2. Neuregulin-1beta (NRG-1beta) induced Tyr-phosphorylation of both ErbB4 and ErbB2. We also found differences in the signaling cascades activated by each growth factor. To stress the perfused mouse heart, we combined EPI with low-flow ischemia. This resulted in (i) loss of left ventricle contraction force ( + dP/dt(max)) and developed pressure (LVDP) after a short period of hypercontractility, (ii) enhanced anaerobic metabolism (lactate production), and (iii) myocyte injury (lactate dehydrogenase (LDH) release). EGF and NRG-1beta had different effects on stressed-heart contractility. EGF reduced to a half the loss of both + dP/dt(max) and LVDP. In contrast, NRG-1beta exacerbated the hypercontractility soon after reperfusion. This is coincident with a transient increase in coronary flow after reperfusion. In spite of these differences in contraction, both EGF and NRG-1beta induced similar early protection as shown by the reduction of LDH release. Our results show that the ErbB system protects the perfused heart against damage induced by acute stress. They reinforce the relevance of ErbB receptors and ligands in cardiac physiology.
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PMID:ErbB receptors protect the perfused heart against injury induced by epinephrine combined with low-flow ischemia. 1937 Apr 75

Ischemic injury of the heart is associated with activation of multiple signal transduction systems including the heterotrimeric G-protein system. Here, we report a role of the ischemia-inducible regulator of G betagamma subunit, AGS8, in survival of cardiomyocytes under hypoxia. Cultured rat neonatal cardiomyocytes (NCM) were exposed to hypoxia or hypoxia/reoxygenation following transfection of AGS8siRNA or pcDNA::AGS8. Hypoxia-induced apoptosis of NCM was completely blocked by AGS8siRNA, whereas overexpression of AGS8 increased apoptosis. AGS8 formed complexes with G-proteins and channel protein connexin 43 (CX43), which regulates the permeability of small molecules under hypoxic stress. AGS8 initiated CX43 phosphorylation in a G betagamma-dependent manner by providing a scaffold composed of G betagamma and CX43. AGS8siRNA blocked internalization of CX43 following exposure of NCM to repetitive hypoxia; however it did not influence epidermal growth factor-mediated internalization of CX43. The decreased dye flux through CX43 that occurred with hypoxic stress was also prevented by AGS8siRNA. Interestingly, the G betagamma inhibitor Gallein mimicked the effect of AGS8 knockdown on both the CX43 internalization and the changes in cell permeability elicited by hypoxic stress. These data indicate that AGS8 is required for hypoxia-induced apoptosis of NCM, and that AGS8-G betagamma signal input increased the sensitivity of cells to hypoxic stress by influencing CX43 regulation and associated cell permeability. Under hypoxic stress, this unrecognized response program plays a critical role in the fate of NCM.
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PMID:Activator of G protein signaling 8 (AGS8) is required for hypoxia-induced apoptosis of cardiomyocytes: role of G betagamma and connexin 43 (CX43). 1972 22

Previous studies have suggested that intravenous transplantation of mesenchymal stem cells (MSCs) in rat ischemia models reduces ischemia-induced brain damage. Here, we analyzed the expression of neurotrophic factors in transplanted human MSCs and host brain tissue in rat middle cerebral artery occlusion (MCAO) ischemia model. At 1 day after transient MCAO, 3 x 10(6) immortalized human MSC line (B10) cells or PBS was intravenously transplanted. Behavioral tests, infarction volume, and B10 cell migration were investigated at 1, 3, 7, and 14 days after MCAO. The expression of endogenous (rat origin) and exogenous (human origin) neurotrophic factors and cytokines was evaluated by quantitative real-time RT-PCR and Western blot analysis. Compared with PBS controls, rats receiving MSC transplantation showed improved functional recovery and reduced brain infarction volume at 7 and 14 days after MCAO. In MSC-transplanted brain, among many neurotrophic factors, only human insulin-like growth factor 1 (IGF-1) was detected in the core and ischemic border zone at 3 days after MCAO, whereas host cells expressed markedly higher neurotrophic factors (rat origin) than control rats, especially vascular endothelial growth factor (VEGF) at 3 days and epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) at 7 days after MCAO. Intravenously transplanted human MSCs induced functional improvement, reduced infarct volume, and neuroprotection in ischemic rats, possibly by providing IGF-1 and inducing VEGF, EGF, and bFGF neurotrophic factors in host brain.
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PMID:Transplantation of human mesenchymal stem cells promotes functional improvement and increased expression of neurotrophic factors in a rat focal cerebral ischemia model. 1988 63

The role of ErbB4 and ErbB2 in the heart of adult mammals is well established. The heart also expresses ErbB1 (the epidermal growth factor (EGF) receptor), but this receptor has received less attention. We studied the effect of EGF on the response of isolated mouse heart to low-flow ischemia and reperfusion. Reducing perfusate flow to 10% for 30 min resulted in an increase in anaerobic metabolism and the leakage of lactate dehydrogenase during reperfusion. In addition, left ventricle +dP/dt and developed pressure were depressed (20-25%) during reperfusion. The addition of EGF 5 min before and throughout the ischemic period prevented the increase in anaerobic metabolism and the leakage of intracellular lactate dehydrogenase during reperfusion. EGF improved both +dP/dt and developed pressure during ischemia and prevented the decrease in dP/dt during reperfusion. To determine whether the effect of EGF on cell integrity depends on its effect on contractility, we studied nonbeating isolated myocytes. In these cells, anoxia and reoxygenation reduced cell viability by nearly 25%. EGF prevented such a decrease. Our results indicate that, like ErbB4 and ErbB2, ErbB1 also has an important role in the heart of adult animals.
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PMID:Epidermal growth factor protects the heart against low-flow ischemia-induced injury. 2042 37

Diabetes is increasing in the world and causes severe cardiovascular complications. Diabetes-induced limb ischemia leads to foot amputation and therapeutic remedies are urgently needed. Here we report that local injection of mesenchymal stem cells (MSCs) prestimulated with epidermal growth factor (EGF) restored blood flow and vasculogenesis in the ischemic hind-limb of type II diabetic (db(-)/db(-)) mice. Bone marrow cells from db(-)/db(-) mice are altered as evidenced by increased oxidative stress and reduced Akt and adhesion molecules when compared with control (db(-)/db(+)). Femoral artery ligation-induced ischemia was performed in the hind-limb of db(-)/db(-) and db(-)/db(+) mice for 28 days. Enhanced green fluorescent protein (EGFP)-MSCs stimulated+/-exogenous EGF for 24 h were injected locally into the ischemic muscle. Blood flow measured with MoorLDI-Laser and microangiography assessed with X-ray showed 100% recovery in db(-)/db(+) compared to 50% recovery in db(-)/db(-) mice. Interestingly, db(-)/db(-) mice had 60 and 96% blood flow recovery and 61 and 98% of vasculogenesis when treated with MSCs alone or MSCs modified with EGF, respectively. Western blot analysis of hind-limb muscles revealed an increase in Akt and vascular endothelial growth factor receptor phosphorylation and hypoxia-inducible factor) expression in db(-)/db(-) mice injected with MSCs or MSCs+EGF compared to db(-)/db(-) mice. Fluorescent microscopic images show that EGFP-MSCs differentiate into new microvessels. Adhesion and migration of MSCs on cultured endothelial cells were ICAM1-, VCAM1- and Akt-dependent mechanism and elevated when MSCs were prestimulated with EGF compared with nonstimulated MSCs. Our novel study data provide evidence that in type II diabetes, stimulated MSCs with EGF enhance the recovery of blood flow and angiogenesis.
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PMID:Modified multipotent stromal cells with epidermal growth factor restore vasculogenesis and blood flow in ischemic hind-limb of type II diabetic mice. 2044 Feb 73

Recovery from ischemic acute kidney injury requires the replacement of damaged tubular cells. This repair process involves epidermal growth factor (EGF) synthesized in medullary the thick ascending limbs (mTAL) of Henle. Atrial natriuretic peptide (ANP), a hormone synthesized by the cardiac atria, increases glomerular filtration rate and renal medullary blood flow. However, the effects of ANP on renal recovery after I/R-induced renal injury remain unclear. We therefore examined whether human ANP enhances recovery from I/R-induced renal injury by reducing damage to EGF-producing kidney cells in a rat model. Male Wistar rats weighing 200-240 g were observed for 48 h after reperfusion following 45-min renal ischemia. Rats were intravenously administered alpha-human ANP (alpha-hANP) at 0.2 microg/kg/min beginning immediately after ischemia and continuing for 2 h after reperfusion. Outer medullary blood flow (OMBF), EGF mRNA, serum blood urea nitrogen (BUN) and creatinine levels as indicators of glomerular function were measured, while urinary N-acetyl beta-D-glucosaminidase (NAG) was used as a specific indicator of proximal tubular function. OMBF was increased by alpha-hANP after reperfusion and maintained significantly higher mRNA level of EGF in the kidney 24 h after reperfusion. I/R-induced increases in serum concentrations of BUN and creatinine and urinary concentrations of NAG were also reduced by alpha-hANP, with improved histopathological changes, including acute tubular necrosis at 24-48 h after reperfusion. This report is the first to demonstrate that alpha-hANP accelerates recovery following renal ischemic insult by reducing the damage to EGF-producing kidney cells.
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PMID:Atrial natriuretic peptide enhances recovery from ischemia/reperfusion-induced renal injury in rats. 2047 88

Acute kidney injury (AKI) is a common disorder associated with high morbidity and mortality rates. Ischemia is the leading cause of AKI. This is a pilot study investigating the ability of multiple urinary cytokines to predict renal functional outcome and mortality in patients with ischemic AKI. Urine samples were obtained from 45 subjects with ischemic AKI on the day of renal consultation and 3 days later. The urinary concentrations of interleukin (IL)-1beta, IL-6, IL-8, monocyte chemotactic protein (MCP)-1, interferon-inducible protein (IP)-10, regulated on activation, normal T-expressed and secreted (RANTES), transforming growth factor (TGF)-alpha, vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF) were measured simultaneously using a microsphere-based immunofluorescence assay. Urinary cytokine levels (pg/mg urine creatinine), which predict renal functional recovery or no recovery the next day and 7 days and 3 months later, were identified. Increased urinary IP-10 and IL-8 predicted no renal functional recovery the next day. Increased urinary IP-10 and VEGF predicted no renal recovery by 7 days. Increased urinary IP-10 and VEGF predicted no renal recovery by 4 days, whereas increased urinary EGF predicted renal functional recovery at that time. Increased urinary IL-8, MCP-1, IP-10, RANTES, EGF, and VEGF predicted patient's death within 3 months. Our findings suggest that urinary IP-10, IL-8, VEGF, TGF-alpha, and EGF may predict renal functional outcome at various times along the course of ischemic AKI and that urinary IL-8, MCP-1, IP-10, RANTES, EGF, and VEGF may predict mortality of the patients within 3 months.
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PMID:Simultaneous monitoring of multiple urinary cytokines may predict renal and patient outcome in ischemic AKI. 2054 Jun 38

Heparin-binding epidermal growth factor EGF-like growth factor (HB-EGF) is a member of the epidermal growth factor family that is expressed in many cell types. We have previously reported the effects of HB-EGF on intestinal epithelial cells and endothelial cells after exposure to ischemia/reperfusion in vivo or anoxia/reoxygenation injury in vitro. However, the effect of HB-EGF on neuronal cells is largely unexplored. In this study, we examined the effect of HB-EGF on neurite outgrowth in pheochromocytoma (PC12) cells as well as the neuroprotective effect of HB-EGF on injured PC12 cells exposed to oxygen and glucose deprivation (OGD), which mimics ischemic conditions. We found that HB-EGF significantly promotes PC12 cell neurite outgrowth and that this effect was blocked by EGF receptor (EGFR) inhibition or mitogen-activated protein kinase (MAPK) inhibition, but not by tyrosine kinase inhibition. In the face of OGD injury, HB-EGF preserves cell viability and decreases apoptosis and LDH release in PC12 cells. HB-EGF-mediated cytoprotection was abolished by EGFR inhibition and MAPK inhibition. We conclude that HB-EGF, through its interaction with the EGF receptor, activates the MAPK signaling pathway in PC12 cells under basal or injury conditions, leading to enhanced neurite outgrowth and neuroprotection against ischemic injury.
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PMID:Heparin-binding epidermal growth factor-like growth factor is a potent neurotrophic factor for PC12 cells. 2084 49


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