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

Adrenomedullin (ADM) is a 52-amino acid peptide with structural homology to calcitonin gene-related peptide (CGRP) initially isolated from human pheochromocytoma. ADM is synthesized by many mammalian tissues including the adrenal medulla, endothelial and vascular smooth muscle cells, myocardium and central nervous system. ADM binds to plasma membrane receptors composed of calcitonin receptor-like receptor (CRLR), a member of serpentine receptor superfamily, and receptor activity modifying protein (RAMP) type 2 or 3. ADM has also some affinity for CGR(1) receptor composed of CRLR and RAMP1. ADM dilates blood vessels in both endothelium-dependent and independent manner and decreases systemic arterial pressure. Intrarenally administered ADM increases natriuresis by vascular and tubular mechanisms. In addition, ADM inhibits migration and proliferation of vascular smooth muscle cells and attenuates myocardial remodelling by inhibiting protein synthesis in cardiomyocytes and proliferation of cardiac fibroblasts. ADM is expressed in various tissues from early stage of embryogenesis and is also synthesized in placenta, uterus and fetal membranes. Plasma ADM level is increased in arterial hypertension, acute coronary syndromes, heart failure, renal diseases and septic shock, being involved in the pathophysiology of these disorders. Experimental ADM treatment is beneficial in arterial and pulmonary hypertension, heart failure, septic shock and ischemia/reperfusion injury. Proadrenomedullin N-terminal peptide (PAMP) is another product of ADM gene which is co-secreted by ADM-producing tissues, with some effects similar and some opposite to ADM.
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PMID:Adrenomedullin--what do we know 10 years since its discovery? 1504 74

The neuroactive steroids dehydroepiandrosterone (DHEA), its sulfate ester DHEA sulfate (DHEAS), and allopregnanolone (Allo), produced by the CNS and the adrenals, appear to exert a protective effect in hippocampal and cortical neuron ischemia- and excitotoxicity-induced injury. We hypothesized that they may also play a protective role on the adrenal medulla, an important part of the sympathetic nervous system, and the tissue adjacent to their primary site of production. DHEA, DHEAS, and Allo protected rat chromaffin cells and the rat pheochromocytoma PC12 cell line, an established model for the study of adrenomedullary cell apoptosis and survival, against serum deprivation-induced apoptosis. Their effects were time- and dose-dependent, with EC50 1.8, 1.1, and 1.5 nM, respectively. The antiapoptotic effect of DHEA DHEAS and Allo was compared to that of a long list of structurally related compounds and was found to be structure-specific, confined mainly to conformation 3beta-OH-Delta5 for androstenes and 3alpha-OH for pregnanes. Indeed, 3-keto, Delta4, or C7 hydroxylated androstenes and 3beta pregnanes were ineffective. The prosurvival effect of DHEA(S) and Allo was N-methyl-D-aspartate-, GABAA-, sigma1-, or estrogen receptor-independent. It involved the antiapoptotic Bcl-2 proteins, their role being sine qua non for their action because Bcl-2 antisense oligonucleotides reversed their effects. Finally, DHEA(S) and Allo activated cAMP response element-binding protein and NF-kappaB, upstream effectors of antiapoptotic Bcl-2 protein expression. They also activated the antiapoptotic kinase PKCalpha/beta, a posttranslational activator of Bcl-2 protein. Our findings suggest that decline of DHEA(S) and Allo during aging or stress may leave the adrenal medulla unprotected against proapoptotic challenges.
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PMID:Dehydroepiandrosterone and allopregnanolone protect sympathoadrenal medulla cells against apoptosis via antiapoptotic Bcl-2 proteins. 1514 90

Magnesium-dependent neutral sphingomyelinase (N-SMase) present in plasma membranes is an enzyme that can be activated by stress in the form of inflammatory cytokines, serum deprivation, and hypoxia. The design of small molecule N-SMase inhibitors may offer new therapies for the treatment of inflammation, ischemic injury, and cerebral infarction. Recently, we synthesized a series of difluoromethylene analogues (SMAs) of sphingomyelin. We report here the effects of SMAs on the serum/glucose deprivation-induced death of neuronally differentiated pheochromocytoma (PC-12) cells and on cerebral infarction in mice. SMAs inhibited the enhanced N-SMase activity in the serum/glucose-deprived PC-12 cells, and thereby suppressed the apoptotic sequence: ceramide formation, c-Jun N-terminal kinase phosphorylation, caspase-3 activation, and DNA fragmentation in the nuclei. Administration of SMA-7 (10 mg/kg i.v.) with IC50= 3.3 microM to mice whose middle cerebral arteries were occluded reduced significantly the size of the cerebral infarcts, compared to the control mice. These results suggest that N-SMase is a key component of the signaling pathways in cytokine- and other stress-induced cellular responses, and that inhibiting or stopping N-SMase activity is an important strategy to prevent neuron death from ischemia.
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PMID:Inhibition of sphingomyelinase activity helps to prevent neuron death caused by ischemic stress. 1523 3

It is widely, but mistakenly, believed that ischemic heart disease (IsHD) and its complications are the sole and direct result of reduced coronary blood flow by obstructive coronary artery disease (CAD). However, cardiac angina, acute myocardial infarction (AMI), and sudden cardiac death (SCD) occur in 15%-20% of patients with anatomically unobstructed and grossly normal coronaries. Moreover, severe obstructive coronary disease often occurs without associated pathologic myocardiopathy or prior symptoms, ie, unexpected sudden death, silent myocardial infarction, or the insidious appearance of congestive heart failure (CHF). The fact that catecholamines explosively augment oxidative metabolism much more than cardiac work is generally underappreciated. Thus, adrenergic actions alone are likely to be more prone to cause cardiac ischemia than reduced coronary blood flow per se. The autonomic etiology of IsHD raises contradictions to the traditional concept of anatomically obstructive CAD as the lone cause of cardiac ischemia and AMI. Actually, all the signs and symptoms of IsHD reflect autonomic nervous system imbalance, particularly adrenergic hyperactivity, which may by itself cause ischemia as in rest angina. Adrenergic activity causing ischemia signals cardiac pain to pain centers via sympathetic efferent pathways and tend to induce arrhythmogenic and necrotizing ischemic actions on the cardiovascular system. This may result in ischemia induced metabolic myocardiopathy not unlike that caused by anatomic or spasmogenic coronary obstruction. The clinical study and review presented herein suggest that adrenergic hyperactivity alone without CAD can be a primary cause of IsHD. Thus, adrenergic heart disease (AdHD), or actually adrenergic cardiovascular heart disease (ACVHD), appears to be a distinct entity, most commonly but not necessarily occurring in parallel with CAD. CAD certainly contributes to vulnerability as well as the progression of IsHD. This vicious cycle, which explains the frequent parallel occurrence of arteriosclerosis and IHD, an association that appears to be linked by the same cause, comprises a common vulnerability to deleterious adrenergic actions on the myocardium, lipid metabolism, and vascular system alike, rather than viewing CAD and IsHD as having a putative cause and effect relationship as commonly thought. Adrenergic actions can also cause the abnormal lipid metabolism that is associated with CAD and IsHD by catecholamine-induced metabolic actions on lipid mobilization by activation of phospholipases. This may also be part of toxic catecholamine hypermetabolic actions by enhancing deleterious cholesterol and lipid actions in damaging coronary vessels by plaque formation as well as inducing obstructive coronary spasm and platelet aggregation. This may also cause direct toxic necrosis on the myocardium as well as atherosclerosis in blood vessels. In fact, drugs that inhibit adrenergic actions like propranolol, reserpine, and guanethidine all inhibit arteriosclerosis induced by hypercholesterolemia in experimental animals and prevent carotid vascular disease (associated with stroke) in humans. The concomitant development of myocardiopathy and coronary vascular lesions or coronary and carotid artery intimal medial thickening by catecholamine toxicity is reflected by the frequent primary presentation of patients with catecholamine-secreting pheochromocytoma with cardiovascular disease, ie, hypertension arrhythmias, AMI, SCD, CHF, and vascular disease, which represents a clear example of the primary deleterious impact of catecholamines on the entire cardiovascular system causing adrenergic cardiovascular disease. Thus, like myocardiopathy, CAD and atherosclerosis in general may be the consequences of or a complication of catecholamine actions rather than its putative cause. This report shows how prophylactic bretylium not only prevents arrhythmias but prevents myocardial necrosis, shock, CHF, maintains or restores normal contractility, and lowers mortality in AMI patients by inducing adrenergic blockade.
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PMID:Prevention of ventricular fibrillation, acute myocardial infarction (myocardial necrosis), heart failure, and mortality by bretylium: is ischemic heart disease primarily adrenergic cardiovascular disease? 1535 32

Although ischemic tolerance has been described in a variety of primary cell culture systems, no similar in vitro models have been reported with any cell line. A model of ischemic preconditioning in the rat pheochromocytoma PC12 cell line is described here. When compared to nonpreconditioned cells, preexposure of PC12 cells to 6 hours of oxygen and glucose deprivation (OGD) significantly increased cell viability after 15 hours of OGD 24 hours later. Flow cytometry analysis of cells labeled with specific markers for apoptosis, Annexin V, and Hoechst 33342, and of DNA content, revealed that apoptosis is involved in OGD-induced PC12 cell death and that preconditioning of the cells mainly counteracts the effect of apoptosis. Immunocytochemistry of caspase-3, a central executioner in the apoptotic process, further confirmed the activation of apoptotic pathways in OGD-induced PC12 cell death. This model may be useful to investigate the cellular mechanisms involved in neuronal transient tolerance following ischemia.
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PMID:Development of an ischemic tolerance model in a PC12 cell line. 1564 48

It has been shown that deletion of the gene encoding the inducible form of nitric oxide synthase (iNOS) results in a reduction of ischemia-induced apoptotic cell death, suggesting the detrimental role of iNOS. The signaling pathways by which iNOS mediates apoptotic cell death under ischemic conditions remain unclear. Understanding the molecular mechanisms of iNOS-mediated apoptotic cell death in ischemia may offer opportunities for potential therapeutic intervention. In the current study, undifferentiated rat pheochromocytoma PC12 cells, exposed to oxygen and glucose deprivation (OGD) followed by reperfusion (adding back oxygen and glucose, OGD-R), were used as an in vitro model of ischemia. The iNOS expression and activity were increased during OGD-R. OGD-R-induced apoptosis was demonstrated by the increase of LDH release, cytosolic release of cytochrome C and caspase-3 activity. Inhibition of iNOS activity by selective iNOS inhibitors, aminoguanidine and 1400W, reduces OGD-R-induced apoptotic cell death, as demonstrated by the decrease of LDH release, cytochrome C release, and caspase-3 activity. These results suggest the critical role of iNOS in mediating apoptosis under ischemic conditions, likely through the induction of caspase-3 activity.
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PMID:Inhibitors of iNOS protects PC12 cells against the apoptosis induced by oxygen and glucose deprivation. 1566 23

Adrenomedullin (AM) is a potent, long-lasting vasodilator peptide that was originally isolated from human pheochromocytoma. AM signaling is of particular significance in endothelial cell biology since the peptide protects cells from apoptosis, promotes angiogenesis, and affects vascular tone and permeability. The angiogenic effect of AM is mediated by activation of Akt, mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2, and focal adhesion kinase in endothelial cells. Both AM and its receptor, calcitonin receptor-like receptor, are upregulated through a hypoxia-inducible factor-1-dependent pathway under hypoxic conditions. Thus AM signaling plays an important role in the regulation of angiogenesis in hypoxic conditions. Recently, we have developed a nonviral vector, gelatin. Positively charged gelatin holds negatively charged plasmid DNA in its lattice structure. DNA-gelatin complexes can delay gene degradation, leading to efficient gene transfer. Administration of AM DNA-gelatin complexes induces potent angiogenic effects in a rabbit model of hindlimb ischemia. Thus gelatin-mediated AM gene transfer may be a new therapeutic strategy for the treatment of tissue ischemia. Endothelial progenitor cells (EPCs) play an important role in endothelial regeneration. Interestingly, EPCs phagocytose ionically linked DNA-gelatin complexes in coculture, which allows nonviral gene transfer into EPCs. AM gene transfer into EPCs inhibits cell apoptosis and induces proliferation and migration, suggesting that AM gene transfer strengthens the therapeutic potential of EPCs. Intravenous administration of AM gene-modified EPCs regenerate pulmonary endothelium, resulting in improvement of pulmonary hypertension. These results suggest that in vivo and in vitro transfer of AM gene using gelatin may be applicable for intractable cardiovascular disease.
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PMID:Adrenomedullin: angiogenesis and gene therapy. 1588 52

Beta-amyloid peptide (Abeta) is considered responsible for the pathogenesis of Alzheimer's disease (AD). Several lines of evidence support that Abeta-induced cytotoxicity is mediated through the generation of reactive oxygen species (ROS). Thus, agents that scavenge ROS level may usefully impede the development or progress of AD. Green tea extract has been known to have such antioxidant properties. Our previous studies demonstrate that green tea extract protected ischemia/reperfusion-induced brain cell death by scavenging oxidative damages of macromolecules. In this study, we investigated the effects of green tea extract on Abeta-induced oxidative cell death in cultured rat pheochromocytoma (PC12) cells. PC12 cells treated with Abeta25-35 (10-50 microM) showed intracellular ROS elevation, the formation of 8-oxodG (an oxidized form of DNA), and underwent apoptotic cell death in a dose-dependent manner. Abeta(25-35) treatment upregulated pro-apoptotic p53 at the gene level, and Bax and caspase-3 at the protein level, but downregulated anti-apoptotic Bcl-2 protein. Interestingly, co-treated green tea extract (10-50 microg/ml) dose-dependently attenuated Abeta(25-35) (50 microM)-induced cell death, intracellular ROS levels, and 8-oxodG formation, in addition to p53, Bax, and caspase-3 expression, but upregulated Bcl-2. Furthermore, green tea extract prevented the Abeta(25-35)-induced activations of the NF-kappaB and ERK and p38 MAP kinase pathways. Our study suggests that green tea extract may usefully prevent or retard the development and progression of AD.
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PMID:Inhibitory effect of green tea extract on beta-amyloid-induced PC12 cell death by inhibition of the activation of NF-kappaB and ERK/p38 MAP kinase pathway through antioxidant mechanisms. 1615 42

Neurodegenerative disorders and chronic disability due to stroke in the brain or spinal cord afflict a large sector of the population. To investigate the mechanism involved in ischemic stroke and to develop neuroprotective drugs/therapies, in vivo and in vitro, pharmacological models are needed. To investigate the cellular and molecular neuroprotective mechanisms of nerve growth factor (NGF), a member of the nervous system neurotrophin family of growth factors, under ischemia, we used an oxygen-glucose-deprivation (OGD) device and pheochromocytoma PC12 cells exposed to a paradigm of ischemic insult. Pretreatment of the cultures with 50 ng/mL of NGF, 18 h prior to OGD insult, conferred 30% of neuroprotection. Time-course experiments showed marked activation of the ERK, JNK, and p-38 MAPK isoforms during the OGD phase, but not during OGD reperfusion. Pretreatment of the cultures with 50 ng/mL of NGF, 18 h prior to OGD insult, resulted in 50% attenuation of OGD-induced activation of JNK 1, and 20% and 50% attenuation of OGD-induced activation of p-38 alpha and beta, respectively. The effect of NGF on gene expression in the PC12 ischemic model using Affymatrix Rat DNA-Microarray technology indicates that only 6% of the genes are differentially regulated (induced/suppressed) by OGD insult and/or NGF. These findings support the notion that pretreatment with NGF confers neuroprotection from OGD insult, a phenomenon coincidentally related to differential inhibition of MAPK stress kinase isoforms and differential gene expression. This ischemic model may be useful to investigate molecular mechanisms of OGD-induced neurotoxicity and NGF-induced neuroprotection, and to generate novel therapeutic concepts for stroke treatment.
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PMID:Neuroprotection by NGF in the PC12 in vitro OGD model: involvement of mitogen-activated protein kinases and gene expression. 1617 11

Our previous data indicate that ischemia and amyloid beta peptide (A beta) cause an oxidative damage to macromolecules. In the present study we investigated the role of p53 protein in cell survival and death after administration of A beta. The experiments were carried out on pheochromocytoma cells (PC-12) and cortical primary neurons in culture. The cortical neurons were exposed (48 h, 10 microM) to the action of a short A beta 25-35 neurotoxic fragment and the involvement of p53 was evaluated after addition of the p53 inhibitor pifithrin-alpha. Changes in cell morphology were evaluated by 4', 6-diamidino-2-phenylindole staining and the concentration-dependent effect of pifithrin-alpha on cells viability was determined. Additionally, we studied the effect of pifithrin-alpha on neuronal survival in vivo after a 5-min global brain ischemia followed by 7 days' reperfusion in gerbils. We found that A beta enhanced apoptotic cell death in cortical primary neurons. Pifithrin-alpha, at a 10 microM final concentration, protected the neuronal cells from the apoptotic death. However, at concentrations of 0.1 and 1 mM, the p53 inhibitor decreased PC-12 cells' viability in a dose-dependent manner. In in vivo experiments we did not observe any neuroprotection by pifithrin-alpha in the CA1 hippocampal layer, which suggests that its effects strongly depend on the duration and type of an ischemic insult. Our data indicate that pifithrin-alpha affects neuronal cells in a dual manner. It has a protective effect at a low concentration, but becomes neurotoxic at higher concentrations.
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PMID:Effects of p53 inhibitor on survival and death of cells subjected to oxidative stress. 1620 96


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