Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Brain angiotensin II (Ang II) plays a key role in blood pressure control in part by interacting with catecholamines (CA) and by stimulation of sympathetic pathways. The significance of Ang-CA interaction is further heightened by the presence of a hyperactive brain Ang II system in spontaneously hypertensive (SH) rat, a genetic model for essential hypertension. Neuronal cells in primary culture from the hypothalamus-brainstem that mimic in vivo situations in so far as many cellular actions of Ang II are concerned, have been used in the present study to elucidate Ang II regulation of CA by determining its cellular action on the norepinephrine transporter (NET) system. Ang II causes both acute and chronic stimulation of [3H]-norepinephrine (NE) uptake in neuronal cultures of Wistar Kyoto (WKY) rat brain. Acute stimulation begins as early as 5 min, reaches maximal levels in about 30 min in the presence of 100 nM Ang II, and is blocked by losartan, a specific antagonist for AT1 receptor subtype. In addition, this acute stimulation appears to be a posttranscriptional event and does not involve protein kinase C (PKC) or NET gene transcription. Chronic stimulation of [3H]-NE uptake by Ang II persists throughout the duration of Ang II incubation (24 h), is dose dependent, and is also mediated by AT1 receptor subtype. However, chronic stimulation of [3H]-NE uptake involves PKC, cfos, and NET gene transcription. Ang II also stimulates [3H]-NE uptake in neuronal cultures of SH rat brain, both acutely and chronically, by mechanisms similar to those observed in neuronal cultures of WKY rat brain. The stimulation of NET by Ang II is 2-fold higher than that seen in WKY and is consistent with increased AT1 receptor gene transcription and increased functional AT1 receptors in SH rat brain neurons compared with WKY rat brain neurons. The Ang II stimulation of the NET system is also higher in adult SH compared with WKY rats in vivo. These observations show that 1) Ang II stimulates the NET system both acutely and chronically, the former involving activation of preexisting transporters and the latter involving NET gene transcription and translation; and 2) Ang II stimulation of the NET system is elevated in SH rat brain neurons.
 ...
PMID:Regulation of norepinephrine transport system by angiotensin II in neuronal cultures of normotensive and spontaneously hypertensive rat brains. 859 28

Neuronal cells in primary culture from the hypothalamus-brain stem areas of normotensive [Wistar-Kyoto (WKY)] and spontaneously hypertensive (SH) rat brains have been used in the present study to investigate an interaction between the brain renin-angiotensin II system and the plasminogen activator system. This is an attempt to further our understanding of the role of brain Ang II in the control of neuronal development and differentiation through its regulation of the extracellular matrix. Ang II caused a 10-fold stimulation of plasminogen activator inhibitor-1 (PAI-1) messenger RNA (mRNA) in WKY rat brain neuronal cultures. The stimulation was mediated by the AT1 receptor subtype and was accompanied by an increase in PAI-1 gene transcription and the synthesis of cellular PAI-1 protein. The stimulation involved activation of protein kinase C, and alterations in the intracellular Ca2+ pool caused a significant inhibition of Ang II stimulation of PAI mRNA. Ang II stimulation of PAI-1 mRNA succeeded its action on c-fos mRNA and was attenuated by c-fos antisense oligonucleotide. Although PAI-1 gene expression was also stimulated by Ang II in neuronal cultures of SH rat brain, two differences between WKY and SH rat brain neurons were observed: 1) the level of Ang II stimulation in SH rat neurons was 50% of that in WKY rat neurons; and 2) Ang II stimulation of c-fos was 2.4-fold higher in SH neurons than in WKY neurons, but c-fos antisense oligonucleotide did not attenuate the stimulatory action of Ang II on PAI-1 mRNA in SH neurons. These observations suggest that the changes in the Ang II-mediated signaling pathways and/or the regulatory region(s) of the PAI-1 gene may contribute to the differential actions of Ang II in WKY and SH rat brain neurons.
 ...
PMID:Angiotensin II regulation of plasminogen activator inhibitor-1 gene expression in neurons of normotensive and spontaneously hypertensive rat brains. 864 Dec 4

In the present study we investigated the regulation of tyrosine hydroxylase (TH) by angiotensin II (Ang II) in an attempt to provide cellular and molecular evidence that this hormone has increased neuromodulatory actions in the spontaneously hypertensive (SH) rat brain. Neuronal cells in primary culture from the hypothalamus-brain stem of both normotensive [Wistar-Kyoto (WKY)] and SH rats have been used. These cultures mimic in vivo situations. Ang II caused a time-dependent increase in TH activity in WKY rat brain neurons. A maximal increase of 2.5-fold was observed with 100 nM Ang II in an actinomycin- and cycloheximide-dependent process. In addition, Ang II caused a parallel increase in TH messenger RNA (mRNA) levels, with a maximal stimulation of 5-fold in 4 h by 100 nM Ang II in WKY rat brain neurons. The stimulation of TH mRNA was mediated by the AT1 receptor subtype, resulted from an increase in its transcription, and involved activation of phospholipase C and protein kinase C. Antisense oligonucleotide for c-fos attenuated Ang II stimulation of TH mRNA in a time- and dose-dependent fashion, indicating an involvement of c-fos as a putative third messenger in Ang II stimulation of TH. Ang II also caused stimulation of TH activity and its mRNA levels in neuronal cultures of SH rat brain by a mechanism similar to that observed for neuronal cultures of WKY rat brain, involving AT1 receptors, protein kinase C, and c-fos. However, the stimulation of TH activity and that of TH mRNA were approximately 30% and 80% higher, respectively, in the SH rat brain neurons than those in the WKY rat brain neurons. In vivo experiments have been carried out to validate the elevated response of TH gene expression to Ang II in SH rat brain neuronal cultures. Ang II stimulated both TH activity and TH mRNA levels in the hypothalami and brain stems of adult WKY and SH rats. The level of stimulation in the brain of the SH rat was significantly higher than that in the WKY rat. These observations are consistent with an increase in AT1, receptor gene expression and suggest that increased TH gene expression could be the cellular/molecular basis for the greater neuromodulatory action of Ang II in the SH rat brain.
 ...
PMID:Angiotensin II regulation of tyrosine hydroxylase gene expression in the neuronal cultures of normotensive and spontaneously hypertensive rats. 875 88

Neuronal degeneration, gonadal abnormalities, and immune deficiency are some of the major manifestations of the hereditary disease ataxia telangiectasia, which is caused by mutations in a single gene, designated ATM. Here we show that the product of the ATM gene is a 370-kDa nuclear phosphoprotein. Because ATM knockout mice recapitulate the clinical symptoms of the human disease, we have examined ATM gene expression in mice. In mouse embryos at gestation day 13.5, ATM mRNA is expressed ubiquitously, with high levels detected in the nervous system and lung. Elevated ATM mRNA levels were also found in the thymus of mouse embryos at gestation day 18.5, a time when V(D)J recombination is occurring. In adult mice, ATM protein was detected in all tissues examined and was present at elevated levels in the testis, spleen, and thymus. The ATM expression pattern and the nuclear localization of the ATM protein are consistent with the proposed function of ATM in the activation of cell cycle checkpoints, DNA repair, and genetic recombination.
 ...
PMID:The product of the ATM gene is a 370-kDa nuclear phosphoprotein. 896 40

The objective of this review is to examine the role of neuronal angiotensin II (Ang II) receptors in vitro. Two types of G protein-coupled Ang II receptors have been identified in cardiovascularly relevant areas of the brain: the AT1 and the AT2. We have utilized neurons in culture to study the signaling mechanisms of AT1 and AT2 receptors. Neuronal AT1 receptors are involved in norepinephrine (NE) neuromodulation. NE neuromodulation can be either evoked or enhanced. Evoked NE neuromodulation involves AT1 receptor-mediated, losartan-dependent, rapid NE release, inhibition of K+ channels and stimulation of Ca2+ channels. AT1 receptor-mediated enhanced NE neuromodulation involves the Ras-Raf-MAP kinase cascade and ultimately leads to an increase in NE transporter, tyrosine hydroxylase and dopamine beta-hydroxylase mRNA transcription. Neuronal AT2 receptors signal via a Gi protein and are coupled to activation of PP2A and PLA2 and stimulation of K+ channels. Finally, putative cross-talk pathways between AT1 and AT2 receptors will be discussed.
 ...
PMID:Angiotensin receptors and norepinephrine neuromodulation: implications of functional coupling. 955 76

The objective of this review is to examine the role of neuronal angiotensin II (Ang II) receptors in vitro. Two types of G protein-coupled Ang II receptors have been identified in cardiovascularly relevant areas of the brain: the AT1 and the AT2. We have utilized neurons in culture to study the signaling mechanisms of AT1 and AT2 receptors. Neuronal AT1 receptors are involved in norepinephrine (NE) neuromodulation. NE neuromodulation can be either evoked or enhanced. Evoked NE neuromodulation involves AT1 receptor-mediated, losartan-dependent, rapid NE release, inhibition of K+ channels and stimulation of Ca2+ channels. AT1 receptor-mediated enhanced NE neuromodulation involves the Ras-Raf-MAP kinase cascade and ultimately leads to an increase in NE transporter, tyrosine hydroxylase and dopamine beta-hydroxylase mRNA transcription. Neuronal AT2 receptors signal via a Gi protein and are coupled to activation of PP2A and PLA2 and stimulation of K+ channels. Finally, putative cross-talk pathways between AT1 and AT2 receptors will be discussed.
 ...
PMID:Angiotensin receptors and norepinephrine neuromodulation: implications of functional coupling. 965 73

The brain contains both angiotensin II (Ang II) type 1 (AT1) and Ang II type 2 (AT2) receptors. Neuronal AT1 receptors mediate the stimulatory actions of Ang II on blood pressure, water and salt intake, and secretion of vasopressin. In contrast, neuronal AT2 receptors have been implicated in the stimulation of apoptosis and as being antagonistic to AT1 receptors. The physiological actions of Ang II in the brain, whether mediated by AT1 or AT2 receptors, involve changes in neuronal activity that are initiated by changes in the activity of membrane ionic currents and channels. This review focusses on the intracellular signalling pathways that couple neuronal AT1 and AT2 receptors to changes in the activity of membrane K+ and Ca2+ currents and channels. As will become clear from our discussion, the signalling pathways that are modulated by neuronal AT1 and AT2 receptors are quite distinct.
 ...
PMID:Neuronal ion channel signalling pathways: modulation by angiotensin II. 969 73

Mammalian brain contains high densities of angiotensin II (Ang II) type 1 (AT1) receptors, localized mainly to specific nuclei within the hypothalamus and brainstem regions. Neuronal AT1 receptors within these areas mediate the stimulatory actions of central Ang II on blood pressure, water and sodium intake, and vasopressin secretion, effects that involve the modulation of brain noradrenergic pathways. This review focuses on the intracellular events that mediate the functional effects of Ang II in neurons, via AT1 receptors. The signaling pathways involved in short-term changes in neuronal activity, membrane ionic currents, norepinephrine (NE) release, and longer-term neuromodulatory actions of Ang II are discussed. It will be apparent from this discussion that the signaling pathways involved in these events are often distinct.
 ...
PMID:Angiotensin II type 1 receptor-modulated signaling pathways in neurons. 1032 70

The renin-angiotensin system (RAS) is one of the best-studied enzyme-neuropeptide systems in the brain and can serve as a model for the action of peptides on neuronal function in general. It is now well established that the brain has its own intrinsic RAS with all its components present in the central nervous system. The RAS generates a family of bioactive angiotensin peptides with variable biological and neurobiological activities. These include angiotensin-(1-8) [Ang II], angiotensin-(3-8) [Ang IV], and angiotensin-(1-7) [Ang-(1-7)]. These neuroactive forms of angiotensin act through specific receptors. Only Ang II acts through two different high-specific receptors, termed AT1 and AT2. Neuronal AT1 receptors mediate the stimulatory actions of Ang II on blood pressure, water and salt intake, and the secretion of vasopressin. In contrast, neuronal AT2 receptors have been implicated in the stimulation of apoptosis and as being antagonistic to AT1 receptors. Among the many potential effects mediated by stimulation of AT2 are neuronal regeneration after injury and the inhibition of pathological growth. Ang-(1-7) mediates its antihypertensive effects by stimulating the synthesis and release of vasodilator prostaglandins and nitric oxide and by potentiating the hypotensive effects of bradykinin. New data concerning the roles of Ang IV and Ang-(1-7) in cognition also support the existence of complex site-specific interactions between multiple angiotensins and multiple receptors in the mediation of important central functions of the RAS. Thus, the RAS of the brain is involved not only in the regulation of blood pressure, but also in the modulation of multiple additional functions in the brain, including processes of sensory information, learning, and memory, and the regulation of emotional responses.
 ...
PMID:The CNS renin-angiotensin system. 1655 51

Lifestyle-related diseases cause macro-and microangiopathies in the major organs including the brain, heart, kidney, and eye, and as a result, shorten the lifespan. The renin-angiotensin system (RAS) has recently been shown to contribute to the processes of accelerated aging caused by lifestyle-related diseases from visceral obesity in the early stage to late-onset organ damage. Vision-threatening diabetic retinopathy and age-related macular degeneration (AMD), associated with lifestyle-related diseases as risk factors for progression, develop retinal and choroidal neovascularization (CNV), respectively, in their advanced stages. We have found that tissue RAS is activated in the pathogenesis of diabetic retinopathy and CNV, leading to angiotensin type 1 receptor(AT1-R)-mediated expression of inflammation-related molecules including vascular endothelial growth factor (VEGF), intercellular adhesion molecule (ICAM)-1, and monocyte chemotactic protein(MCP)-1. Neuronal dysfunction in diabetic retinopathy is also shown to result from AT1-R-mediated degradation of synaptic proteins. Moreover, we revealed for the first time that the receptor for prorenin [(pro) renin receptor] is expressed in the eye, although prorenin was until recently believed to be just an inactive precursor of renin. Prorenin binds to the receptor that causes dual activation of its intracellular signaling and tissue RAS, and this pathogenic mechanism is termed receptor-associated prorenin system (RAPS)'. We have demonstrated the contribution of RAPS to the pathogenesis of CNV and dual regulation of VEGF and MCP-1 by signal transduction via (pro) renin receptor and AT1-R. Next, we report the potential validity of food factor supplements as a therapeutic strategy for preventing the retinal and choroidal pathologies driven by RAS-induced inflammatory and angiogenic molecules. Functional food factors examined include lutein in yellow-green vegetables, the omega-3 polyunsaturated fatty acid eicosapentaenoic acid purified from fish oil, and red pigment astaxanthin from salmon and shrimp. We recently revealed that these food factors prevent intraocular angiogenesis and inflammation by inhibiting the expression of inflammatory molecules including VEGF, ICAM-1, and MCP-1. Preventive medicine for AMD and diabetic retinopathy, both of which have lifestyle-related diseases as a systemic background, has attracted growing attention. In the present review, we provide biological evidence for RAS inhibition and food factor supplementation in the early intervention for retinal and choroidal pathologies as an 'anti-aging ophthalmology' approach.
 ...
PMID:[Lifestyle-related diseases and anti-aging ophthalmology: suppression of retinal and choroidal pathologies by inhibiting renin-angiotensin system and inflammation]. 1934 85


1 2 Next >>