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)

Genetically obese male Zucker rats have an impaired secretion of GH, coupled to hyperinsulinemia, hyperlipidemia and glucose intolerance. The aim of this study was to evaluate whether a chronic treatment with hexarelin, a synthetic enkephalin-derived hexapeptide with a potent GH-releasing activity, might be able to ameliorate the somatotropic function and reverse some metabolic alterations associated with obesity in male obese Zucker rats. Furthermore, as decreased GH secretion and insulin resistance are associated with increased cardiovascular risk, we also tested the capacity of hexarelin to prevent postischemic ventricular dysfunction in hearts of male obese Zucker rats. Obese and lean male rats of the Zucker strain were treated with hexarelin (80 microgram/kg, b.i.d., s.c.) or saline (1 ml/kg, b.i.d., s.c.) for 30 days. An acute hexarelin injection (80 microgram, s.c.) at the 28th day of treatment elicited a rise in plasma GH levels in ! lean but not in obese rats (pretreated or not with hexarelin); lean rats chronically treated with hexarelin showed a greater increase in plasma GH as compared with control counterparts. At the end of the experiment, pituitary GH mRNA levels were significantly reduced in obese rats and hexarelin administration failed to increase pituitary GH mRNA and IGF-I concentrations in plasma and heart. Chronic treatment with hexarelin increased insulinemia and blood glucose levels in obese but not in lean rats, left unaltered the high triglyceride levels but significantly decreased plasma cholesterol concentrations in obese rats. Heart preparations from lean and obese Zucker rats treated with saline, subjected to low flow ischemia and reperfusion, showed at reperfusion: a) a low recovery of postischemic left ventricular developed pressure (LVDP), coupled to a substantial increase in coronary perfusion pressure, and b) a marked increase in creatine kinase released in the perfusates. Hexare! lin administration for 30 days counteracted the heart ischemic damage both in lean and obese Zucker rats. In fact, the recovery of LVDP at reperfusion was significantly higher than in controls and the increase in coronary resistance was minimal. Collectively, these data indicate that a 30-day treatment with hexarelin was unable to improve somatotropic function in male obese Zucker rats but was successful in decreasing plasma cholesterol concentrations. Hexarelin exerted a cardioprotective effect in both lean and obese rats. The heart-protective activity afforded by the peptide was divorced from any stimulation of the GH axis and is probably exerted through activation of specific cardiac receptors.
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PMID:Endocrine, metabolic and cardioprotective effects of hexarelin in obese Zucker rats. 1097 47

Brief coronary occlusion followed by reperfusion leads to reversible myocardial dysfunction (stunning) which can induce irreversible damage of other organ systems. We studied the effects of pretreatment with recombinant human GH (rhGH) and the GH-secretagogue GHRP-2 on myocardial stunning in a blood-perfused isolated rabbit heart model. In a first set of experiments, effects of bolus rhGH administration (3.5 mg/kg) (n = 5) into the aortic root of unpretreated animals were compared with those of saline (n = 6). In a second set, animals were pretreated for 14 days with SC rhGH 3.5 mg/kg x day (n = 9) or 160 microg/kg x day GHRP-2 (n = 8) in two divided doses. Body weight and plasma concentrations of rhGH, rabbit GH (rGH) and IGF-I were determined before and at the end of 14 days pretreatment. Hearts were excised and submitted to 15 min ischemia followed by 80 min reperfusion, after which postischemic recovery was compared with nonischemic hearts mounted into the same system. At study end, all hearts were snap-frozen to examine markers of apoptosis. Circulating levels of rabbit GH (rGH) remained identical in all animals. Pretreatment with rhGH for 14 days induced a 142 +/- 116% rise of serum IGF-I vs. 8 +/- 15% with GHRP-2 (P < 0.001) and increased body weight with 6.8 +/- 2.5% vs. 3.4 +/- 3.3% with GHRP-2 (P = 0.01). A bolus injection of rhGH did not alter myocardial function compared with saline allowing data from these experiments to be pooled into one ischemic control group for further analysis of the effect of pretreatment. No difference in postischemic recovery of left ventricular systolic function among the unpretreated, rhGH pretreated and GHRP-2 pretreated hearts was apparent. At the end of reperfusion, a 3-fold higher end-diastolic pressure (EDP) persisted in the unpretreated and rhGH pretreated hearts compared with the nonischemic hearts. In the GHRP-2 pretreated hearts, EDP decreased to half the pressure observed in unpretreated and rhGH pretreated hearts (all P < or = 0.02), a level which was indistinguishable from that in the non-ischemic hearts, suggesting full postischemic recovery of diastolic function. There were no signs of increased apoptosis in the experimental groups. In conclusion, 14 days pretreatment with GHRP-2, but not rhGH, protected selectively against the diastolic dysfunction of myocardial stunning in this model. This observation may open perspectives for GH-secretagogues as cardioprotective agents.
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PMID:Pretreatment with growth hormone-releasing peptide-2 directly protects against the diastolic dysfunction of myocardial stunning in an isolated, blood-perfused rabbit heart model. 1108 29

IGF-I and IGF-II are single-chain polypeptide growth factors that regulate pleiotropic cellular responses. We have characterized the effect of recombinant IGF proteins, as well as third-generation adenoviral vectors encoding either IGF-I or IGF-II genes, on cardiomyocyte apoptosis and on angiogenesis. We found that endothelial cells cultured in the presence of the extracellular protein laminin exhibit a robust response to IGF-I and -II proteins via enhanced cell migration and angiogenic outgrowth. Furthermore, IGF vectors greatly enhanced neovascularization in an in vivo Matrigel model. Transduction of cardiomyocytes with the IGF adenoviral vectors resulted in a dose- and time-dependent increase in the expression of IGF-I or IGF-II protein. This correlated with abrogation of apoptosis induced by ischemia-reoxygenation, ceramide, or heat shock with optimal inhibition of approximately 80%. We conclude that gene transfer of IGF-I and IGF-II is a plausible strategy for the local delivery of IGFs to treat ischemic heart disease and heart failure by stimulating angiogenesis and protecting cardiomyocytes from cell death.
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PMID:Gene therapy vector-mediated expression of insulin-like growth factors protects cardiomyocytes from apoptosis and enhances neovascularization. 1250 77

The role of brain insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) in neuroprotection was further investigated using in vitro and in vivo models of cerebral ischemia by assessing the effects of IGF-I, IGF-II, and high affinity IGFBP ligand inhibitors (the peptide [Leu24, 59, 60, Ala31]hIGF-I (IGFBP-LI) and the small molecule NBI-31772 (1-(3,4-dihydroxybenzoyl)-3-hydroxycarbonyl-6, 7-dihydroxyisoquinoline), which pharmacologically displace and elevate endogenous, bioactive IGFs from IGFBPs. Treatment with IGF-I, IGF-II, or IGFBP-LI (2 microg/mL) significantly (P < 0.05) reduced CA1 damage in organotypic hippocampal cultures resulting from 35 minutes of oxygen and glucose deprivation by 71%, 60%, and 40%, respectively. In the subtemporal middle cerebral artery occlusion (MCAO) model of focal ischemia, intracerebroventricular (icv) administration of IGF-I and IGF-II at the time of artery occlusion reduced ischemic brain damage in a dose-dependent manner, with maximum reductions in total infarct size of 37% (P < 0.01) and 38% (P < 0.01), respectively. In this model of MCAO, i.c.v. administration of NBI-31772 at the time of ischemia onset also dose-dependently reduced infarct size, and the highest dose (100 microg) significantly reduced both total (by 40%, P < 0.01) and cortical (by 43%, P < 0.05) infarct volume. In the intraluminal suture MCAO model, administration of NBI-31772 (50 microg i.c.v.) at the time of artery occlusion reduced both cortical infarct volume (by 40%, P < 0.01) and brain swelling (by 24%, P < 0.05), and it was still effective when treatment was delayed up to 3 hours after the induction of ischemia. These results further define the neuroprotective properties of IGFs and IGFBP ligand inhibitors in experimental models of cerebral ischemia.
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PMID:Neuroprotective effects of insulin-like growth factor-binding protein ligand inhibitors in vitro and in vivo. 1452 26

Hypoxia preconditioning and subsequent tolerance to hypoxia-ischemia damage is a well-known phenomenon and has significant implications in clinical medicine. In this investigation, we tested the hypothesis that the transcriptional activation of IGF-I is one of the underlying mechanisms for hypoxia-induced neuroprotection. In a rodent model of hypoxia-ischemia, hypoxia preconditioning improved neuronal survival as demonstrated by decreased hypoxia-ischemia-induced neuronal apoptosis. To study the role of IGF-I in hypoxia tolerance, we used in situ hybridization to examine IGF-I mRNA distribution on adjacent tissue sections. In cerebral cortex and hippocampus, hypoxia preconditioning resulted in an increase in neuronal IGF-I mRNA levels with or without hypoxia-ischemia. To test its direct effects, we added IGF-I to primary neuronal culture under varying oxygen concentrations. As oxygen concentration decreased, neuronal survival also decreased, which could be reversed by IGF-I, especially at the lowest oxygen concentration. Interestingly, IGF-I treatment resulted in an activation of hypoxia-inducible factor 1alpha (HIF-1alpha), a master transcription factor for hypoxia-induced metabolic adaptation. To evaluate whether IGF-I transcriptional activation correlates with HIF-1alpha activity, we studied the time course of HIF-1alpha DNA binding activity in the same rat model of hypoxia-ischemia. After hypoxia-ischemia, there was an increase in HIF-1alpha DNA binding activity in cortical tissues, with the highest increase around 24 h. Like IGF-I mRNA levels, hypoxia preconditioning increased HIF-1alpha DNA binding activity alone or with subsequent hypoxia ischemia. Overall, our results suggest that IGF-I transcriptional activation is one of the metabolic adaptive responses to hypoxia, which is likely mediated by a direct activation of HIF-1alpha.
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PMID:Potential role of IGF-I in hypoxia tolerance using a rat hypoxic-ischemic model: activation of hypoxia-inducible factor 1alpha. 1471 2

Insulin-like growth factor-1 (IGF-I), the primary mediator of growth hormone (GH) effects, is an important regulator of cell growth, differentiation, and apoptosis. GH and IGF-I deficiency is known to be associated with premature atherosclerosis and elevated cardiovascular disease mortality. Recent evidence suggests that cardiovascular disease risk may also be elevated among apparently healthy individuals who have serum IGF-I levels in the low-normal range. In this review, we appraise the epidemiologic and clinical studies implicating low IGF-I level as a risk factor for incident myocardial infarction and other manifestations of coronary heart disease. Potential mechanisms that may underlie this association include beneficial effects of IGF-I on myocyte survival after ischemia, stability of atherosclerotic lesions, and endothelial function. We conclude that additional confirmatory data from prospective studies are needed to confirm low IGF-I level as an independent cardiovascular risk factor. However, if this finding is confirmed, this would support the rationale for intervention trials aimed at reducing cardiovascular disease morbidity and mortality among older adults by targeting the GH/IGF-I pathway.
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PMID:Insulin-like growth factors and coronary heart disease. 1559 27

We tested the hypothesis that octreotide, a somatostatin analogue, can mimic ischemic preconditioning (PC) to provide cardioprotection against myocardial infarction. An ischemia-reperfusion model of adult Wistar rats was used. Infarct size was expressed as a percentage of the area at risk under different treatment protocols. Octreotide PC (35 microg/Kg 20 minutes before ischemia-reperfusion) significantly decreased infarct size (18 +/- 4%) versus control (60 +/- 7%). The somatostatin receptor antagonist cyclo-somatostatin (0.5 mg/Kg) could blunt the above cardioprotection. Administration of either chelerythrine (a protein kinase C inhibitor, 2 mg/Kg) or genistein (a tyrosine kinase inhibitor, 5 mg/Kg) could also block octreotide PC (54 +/- 7% and 58 +/- 6%, respectively). Pretreatment with the mitochondrial ATP-sensitive potassium channel antagonist 5-hydroxydecanoic acid (5-HD) and the sarcolemmal ATP-sensitive potassium channel antagonist glibenclamide could abolish the effects of octreotide PC (54 +/- 6% and 52 +/- 6%). Chelerythrine, however, had no effect on octreotide PC. In conclusion, the present study demonstrates that octreotide can mimic ischemic PC to reduce infarct size. Acute effects of octreotide PC involve the activation of protein kinase C, tyrosine kinase C, and mitochondrial ATP-sensitive potassium channels, but not systemic IGF-I activation.
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PMID:Somatostatin analogue mimics acute ischemic preconditioning in a rat model of myocardial infarction. 1577 21

The neocortex and the striatum are the brain regions most known to be particularly vulnerable to acute insults like hypoxia or ischemia. In this work, we assess the possibility of cellular damage to the substantia nigra (SN) after hypoxia-reoxygenation in the new born rat. The aim of the present paper was to evaluate the expression of growth factor IGF-I, and growth factor binding proteins IGFBP-3 and IGFBP-5 genes and induction of NOS family members (nNOS, eNOS and iNOS) and TNF-alpha genes together with glia activation, in the SN at 5 and 48 h after severe hypoxia in the 7 day-old rat, a model for the term human fetus. At early time, while IGFs remain unchanged, we found a transient increase in eNOS and nNOS. Two days after the injury, nNOS expression remained high, iNOS and TNF-alpha increased and also GFAP protein expression was observed together with a profusion of reactive astrocytes distributed throughout the SN. This study on the acute effects of hypoxia on the developing brain provides additional insights into the vulnerability of the SN, a brain region involved in neurodegenerative pathologies.
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PMID:Inflammatory responses of the substantia nigra after acute hypoxia in neonatal rats. 1629 46

The importance of hormone therapy in affording protection against the sequelae of global ischemia in postmenopausal women remains controversial. Global ischemia arising during cardiac arrest or cardiac surgery causes highly selective, delayed death of hippocampal CA1 neurons. Exogenous estradiol ameliorates global ischemia-induced neuronal death and cognitive impairment in male and female rodents. However, the molecular mechanisms by which estrogens intervene in global ischemia-induced apoptotic cell death are unclear. Here we show that estradiol acts via the classical estrogen receptors, the IGF-I receptor, and the ERK/MAPK signaling cascade to protect CA1 neurons in ovariectomized female rats and gerbils. We demonstrate that global ischemia promotes early dephosphorylation and inactivation of ERK1 and the transcription factor cAMP-response element binding protein (CREB), subsequent down-regulation of the antiapoptotic protein Bcl-2, a known gene target of estradiol and CREB, and activation of caspase-3. Estradiol treatment increases basal phosphorylation of both ERK1 and ERK2 in hippocampal CA1 and prevents ischemia-induced dephosphorylation and inactivation of ERK1 and CREB, down-regulation of Bcl-2 and activation of the caspase death cascade. Whereas ERK/MAPK signaling is critical to CREB activation and neuronal survival, the impact of estradiol on Bcl-2 levels is ERK independent. These findings support a model whereby estradiol acts via the classical estrogen receptors and IGF-I receptors, which converge on activation of ERK/MAPK signaling and CREB to promote neuronal survival in the face of global ischemia.
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PMID:MAPK signaling is critical to estradiol protection of CA1 neurons in global ischemia. 1713 46

Exercise increases brain-derived neurotrophic factor (BDNF), phosphorylated cAMP response-element binding protein (pCREB), insulin-like growth factor (IGF-I) and synapsin-I, each of which has been implicated in neuroplastic processes underlying recovery from ischemia. In this study we examined the temporal profile (0, 30, 60 and 120 min following exercise) of these proteins in the hippocampus and sensorimotor cortex following both motorized (60 min) and voluntary (12 h) running, 2 weeks after focal ischemia. Our goal was to identify the optimal training paradigms (intensity, duration and frequency) needed to integrate endurance exercise in stroke rehabilitation. Therefore we utilized telemetry to measure changes in heart rate with both exercise methods. Our findings show that although the more intense, motorized running exercise induced a rapid increase in BDNF, the elevation was more short-lived than with voluntary running. Motorized running was also associated with higher levels of synapsin-I in several brain regions but simultaneously, a more pronounced increase in the stress hormone, corticosterone. Furthermore, both forms of exercise resulted in decreased phosphorylation of CREB and downregulation of synapsin-I in hippocampus beginning 30 to 60 min after the exercise bout. This phenomenon was more robust after motorized running, the method that generated higher heart rate and serum corticosterone levels. This immediate stress response is likely specific to acute exercise and may diminish with repeated exercise exposure. The present data illustrate a complex interaction between different forms of exercise and proteins implicated in neuroplasticity. For clinical application, frequent lower intensity exercise episodes (as in voluntary running wheels), which may be safer to provide to patients with stroke, has a delayed but sustained effect on BDNF that may support brain remodeling after stroke.
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PMID:Exercise intensity influences the temporal profile of growth factors involved in neuronal plasticity following focal ischemia. 1738 14


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