UMLS:C0004135 - FACTA Search

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Using the immunohistochemical localization of the protein product of the immediate early gene, c-fos, to localize activated neurons in the paraventricular nucleus of the hypothalamus (PVN), we studied the chemical phenotypes of neurons activated by circulating angiotensin II (AII). We determined the proportions of activated PVN neurons that expressed AII type I receptor-like immunoreactivity (AT1-L) or the neurohormones vasopressin (VP) and oxytocin (OXY). In addition, we identified activated PVN neurons that putatively produce nitric oxide (NO) on the basis of histochemical staining for nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d). Conscious rats received intravenous AII infusions at a rate sufficient to elevate mean arterial pressure by 40-60 mmHg for 90 min; control rats received infusions of vehicle. Brains were prepared for double immunohistochemistry [Fos-like immunoreactivity (FLI)/AT1-L, FLI/VP or FLI/OXY] or FLI/ NADPH-d histochemistry. Systemic AII infusions led to activation of 149+/-14 PVN neurons per section. In contrast, control animals showed activation of 21+/-6 PVN neurons per section. AII infusions elicited the activation of the following numbers of chemically identified PVN neurons per section: AT1-L, 24+/-5; VP, 26+/-5; OXY, 11+/-2; NADPH-d, 22+/-4. Control animals had few activated PVN neurons per section. For each of the chemically identified populations of PVN neurons, the following proportions were activated: AT1-L, 12.5%; VP, 15.2%; OXY, 7.2%; NADPH-d, 17.3%. The results suggest that PVN neurons producing the AT1 receptor, VP, OXY, and NO, participate in the mediation of the central responses to circulating AII.
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PMID:Activation by systemic angiotensin II of neurochemically identified neurons in rat hypothalamic paraventricular nucleus. 968 48

The purpose of this study was to evaluate the effects of acute (a single injection) and chronic stimulation (twice daily injection for 9 days) by ACTH on changes occurring in the temporal expression of steroidogenic enzymes in the rat adrenal in vivo. Under acute ACTH stimulation, the level of steroidogenic acute regulatory protein (StAR) messenger RNA (mRNA) was increased within 0.5 h in both zona glomerulosa (ZG) and zona fasciculata-reticularis (ZFR), with maximal increases of 220-370% and 300-350% in the ZG and ZFR, respectively. Increases in the levels of StAR protein in homogenates were also found in the ZG (700%) and the ZFR (300%), but were delayed compared with those of their mRNA. Furthermore, the increase in mitochondrial StAR protein was concomitant with that in the homogenate, indicating that the entry of StAR into mitochondria might not be necessary to increase steroidogenesis during the early stimulatory phase. The levels of c-jun, c-fos, junB, and fosB mRNA in ZG and ZFR were also rapidly maximally elevated within 0.5-1 h after ACTH administration and fell to near control levels 5 h posttreatment. The levels of c-jun protein were already increased in both zones at 1 h, reached 200% at 3 h, and remained elevated 5 h post-ACTH treatment. The levels of c-Fos protein were maximally increased by 240% in both zones after 1 h and decreased thereafter to control values at 5 h. Few changes were observed in the adrenal protein contents of cholesterol side-chain cleavage cytochrome P450 (P450scc), cytochrome P450 11beta-hydroxylase (P450C11), cytochrome P450 21-hydroxylase (P450C21), and 3beta-hydroxysteroid dehydrogenase (3betaHSD). Under chronic stimulation by ACTH, we observed elevations in the levels of plasma corticosteroids and changes in the mRNA and protein levels of many adrenal steroidogenic enzymes in both zones. In the ZG, administration of ACTH for 9 days provoked an increase in the level of StAR mRNA (210-270%) and a decrease in the levels of 3betaHSD, cytochrome P450 aldosterone synthase (P450aldo), and AT1 receptor mRNA (by 40%, 70%, and 90%, respectively), whereas the levels of P450scc and P450C21 mRNA did not differ significantly from the control values. Western blotting analysis showed that the adrenal ZG protein levels of StAR and P450scc were increased (150%), 3betaHSD was not changed, and P450C21 was decreased by 70%. In the ZFR, the levels of P450scc and StAR mRNAs were increased (260% and 570-870%, respectively). The levels of 3betaHSD, P450C21, and P450C11 mRNA did not differ from control values in that zone. Western blotting analysis showed that the ZFR protein level of 3betaHSD was not changed, P450scc and P450C21 were decreased by 40% and 60%, respectively, and StAR was increased by 160%. Although c-fos and fosB mRNAs were undetectable after 9 days of chronic ACTH treatment, c-jun mRNA and its protein were still detectable, suggesting a basic role for this protooncogene in maintaining the integrity and function of the adrenal cortex. When dexamethasone was administered to rats for 5 days to inhibit their ACTH secretion, the mRNA levels of many steroidogenic enzymes were decreased, with the exception of StAR, 3betaHSD, and P450aldo. These results confirm the importance of physiological concentrations of ACTH in maintaining normal levels of adrenocortical enzymes and also indicate that in addition to ACTH, other factors are involved in controlling the expression of StAR, 3betaHSD, and P450aldo. In conclusion, we showed that ACTH acutely increases StAR mRNA followed, after a delay, by an increase in the level of StAR protein; this suggests that posttranslational modifications of the StAR precursor occurred during the early stimulatory phase and before the apparent translation of the newly formed mRNA. The rapid induction of protooncogenes suggests their participation in the action of ACTH to stimulate steroidogenesis. (ABSTRACT TRUNCATED)
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PMID:The acute and chronic effects of adrenocorticotropin on the levels of messenger ribonucleic acid and protein of steroidogenic enzymes in rat adrenal in vivo. 972 47

An activated renin-angiotensin system is a major risk factor for cardiovascular events. Angiotensin II acts on AT1 and AT2 receptors. Stimulation of AT1 receptors is associated with endothelial dysfunction, mainly as the consequence of an increased vascular production of superoxide radicals, vasoconstriction, platelet activation, enhanced release of plasminogen activator inhibitor-1, activation of immediate early genes c-fos and c-jun, myocyte hypertrophy, connective tissue formation, endothelin-1 synthesis, and activation of growth factors like PDGF and TGF-beta 1. Stimulation of AT2 receptors can mitigate or abolish the growth promoting effects of AT1 receptor stimulation. The contribution of these effects--single or in combination--on the progression of atherosclerotic lesions, the phenomenon of restenosis and the process of remodeling in heart failure is being progressively elucidated. With increasing knowledge about these relationships the inhibition of AT1 receptors appears as a main target in preventive and reparative strategies in cardiovascular diseases.
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PMID:Angiotensin II and coronary artery disease, congestive heart failure, and sudden cardiac death. 983 71

In C9 (Clone 9) liver cells, angiotensin 11 increased the intracellular Ca2+ content, inositol phosphate production and c-fos mRNA expression. Other angiotensins were also active with the order of potency being angiotensin II = angiotensin III >> angiotensin I > angiotensin IV. Losartan, but not PD 123177 (1-(4-amino-3-methyl)-5-diphenylacetyl-4,5,6,7-tetrahydro-1H-imida zo [4,5c]pyridine-6-carboxylic acid), blocked the effects of angiotensin II. Pertussis toxin did not alter these actions of angiotensin II. These data indicate that the effects were mediated through angiotensin AT1 receptors involving pertussis toxin-insensitive G-proteins. Phorbol myristate acetate was also able to increase c-fos mRNA expression. The action of angiotensin II was consistently greater than that of the active phorbol ester. Staurosporine but not genistein inhibited this effect of angiotensin II. Angiotensin II- and phorbol myristate acetate-induced proto-oncogene mRNA expression was attenuated in cells incubated overnight with the active phorbol ester, which suggests a major role of protein kinase C.
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PMID:Angiotensin AT1 receptors in Clone 9 rat liver cells: Ca2+ signaling and c-fos expression. 987 76

Angiotensin II (Ang II) receptors of the AT1 subtype are coupled to heterotrimeric G nucleotide-binding proteins, G(q/11), to activate phospholipase C-beta isoforms with production of inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol. The resultant release of intracellular Ca2+ and increased Ca2+ influx are major determinants of several acute cellular responses initiated by Ang II, including secretion of aldosterone from the adrenal cortex and smooth muscle contraction. However, cellular events related to more prolonged effects of Ang II, such as hypertrophic and hyperplastic responses, are triggered by intracellular signaling cascades that are less dependent on Ca2+ signals. The Ang II-induced activation of Raf-1 kinase, p42 MAP-kinase and c-fos expression in response to Ang II in adrenal glomerulosa cells does not require Ca2+ influx. Moreover, the dose-response relationships for Raf-1 activation, MAP-kinase activation and mitogenesis show significantly higher sensitivity to Ang II than the InsP3, Ca2+-release and aldosterone secretory responses. The sensitivities of both Raf-1 kinase and MAP-kinase stimulation by Ang II to the inhibitors of phosphoinositide kinases, wortmannin and LY 294002, suggest that inositol phospholipids may play a role in these activation events unrelated to their role in Ca2+ signaling. To investigate the changes of various inositides after stimulation at the single cell level, fluorescent probes were developed in which pleckstrin homology domains with distinct binding specificities to inositol phospholipids were fused to the green fluorescent protein and expressed in NIH 3T3 cells. The use of these probes revealed heterogeneity of the inositol lipid pools and their complex relationship to Ca2+ signals. The use of these tools will help to further clarify the complex role of these lipids in initiating Ca2+-dependent and -independent signaling responses.
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PMID:Signaling events activated by angiotensin II receptors: what goes before and after the calcium signals. 988 5

We raised a polyclonal antibody against a decapeptide corresponding to the carboxyl terminus of the rat angiotensin II AT1 receptor. This antibody was demonstrated to be specific for the rat receptor according to a number of approaches. These included (a) the ultrastructural localization of immunogold-labeled receptor on the surfaces of zona glomerulosa cells in the adrenal cortex, (b) the specific labeling of Chinese hamster ovarian (CHO) cells transfected with AT1 receptors, (c) the identification of a specific band on Western blots, (d) the immunocytochemical co-localization of angiotensin receptors on neurons in the lamina terminalis of the brain shown to be responsive to circulating angiotensin II, as shown by the expression of c-fos, and (e) the correlation between the expression of the mRNA of the AT1 receptor and AT1 receptor immunoreactivity.(J Histochem Cytochem 47:507-515, 1999)
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PMID:Characterization of a specific antibody to the rat angiotensin II AT1 receptor. 1008 52

In response to humoral and mechanical stimuli, the myocardium adapts to increased work load through hypertrophy of individual muscle cells. Myocardial hypertrophy is characterized by an increase in cell size in the absence of cell division and is accompanied by changes in gene expression. Angiotensin II (ANG II), the effector peptide of the renin-angiotensin system (RAS), regulates volume and electrolyte homeostasis and is involved in cardiac and vascular growth in rats. In this review, the role of RAS on the myocyte protein synthesis (myocyte hypertrophy) and on the induction of gene expression will be discussed in rat cardiomyocytes in culture. The traditional RAS can be considered as a system in which circulating ANG II is delivered to target tissues or cells. However, a local RAS has also been described in cardiac cells and evidence has been accumulated for autocrine and/or paracrine pathways by which biological actions of ANG II can be mediated. These actions of ANG II are primarily mediated through ANG II receptors of the subtype I (AT1-R). When evaluating the effects of ANG II in situ, both changes in circulating levels and local production have to be taken into account. Discrepant findings on the in vitro effect of ANG II on the protein synthesis in cardiac myocytes are described and can be at least partly be attributed to methodological problems such as assay of the de novo protein synthesis, isolation and the separation procedure of cardiac myocytes. The ANG II-induced hypertrophic effect also depends on the existence of non-myocytes in a cardiocyte culture. In rat cardiocytes ANG II also causes induction of many immediately-early genes (c-fos, c-jun, jun-B, Egr-1 and c-myc) and induces also late markers of cardiac hypertrophy (skeletal alpha-actin and atrial natriuretic peptide expression) and growth factors (TGF-beta1 gene expression). In vivo ANG II via AT1-R, causes not only ventricular hypertrophy, independently of blood pressure, but also a shift to the fetal phenotype of the myocardium. Angiotensin-converting enzyme inhibitors and ANG II receptor antagonists of the subtype I not only induce the regression, but also prevent the development of cardiac hypertrophy in experimental rat models.
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PMID:Renin-angiotensin system, hypertrophy and gene expression in cardiac myocytes. 1033 36

In response to humoral and mechanical stimuli, the myocardium adapts to increased work load through hypertrophy of individual muscle cells. Myocardial hypertrophy is characterized by an increase in cell size in the absence of cell division and is accompanied by changes in gene expression. Angiotensin II (Ang II), the effector peptide of the renin-angiotensin system (RAS), regulates volume and electrolyte homeostasis and is involved in cardiac and vascular growth in rats. In this review, the role of RAS in myocyte protein synthesis (myocyte hypertrophy) and in induction of gene expression will be discussed in rat cardiomyocytes in culture. Traditional RAS can be considered as a system in which circulating Ang II is delivered to target tissues or cells. However, a local RAS has also been described in cardiac cells and evidence has been accumulated for autocrine and/or paracrine pathways by which biological actions of Ang II can be mediated. These actions of Ang II are primarily mediated through Ang II receptors subtype I (AT1-R). When evaluating the effects of Ang II in situ, both changes in circulating levels and local production have to be taken into account. Contrasting results have been found concerning the in vitro effect of Ang II on the protein synthesis in cardiac myocytes and can be at least partly be attributed to methodological problems such as assay of de novo protein synthesis and isolation and separation procedure of cardiac myocytes. The Ang II-induced hypertrophic effect also depends on the existence of nonmyocytes in a cardiocyte culture. In rat cardiocytes, AngII also causes induction of many immediately-early genes (c-fos, c-jun, jun-B, Egr-1 and c-myc) and induces also late markers of cardiac hypertrophy (skeletal alpha-actin and atrial natriuretic peptide expression) and growth factors (TGF-beta 1 gene expression). In vivo AngII via AT1-R, causes not only ventricular hypertrophy but also a shift to the fetal phenotype of the myocardium. Angiotensin-converting enzyme inhibitors and AngII receptor antagonists of the subtype I not only induce the regression but also prevent the development of cardiac hypertrophy in experimental rat models.
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PMID:Antagonism of the renin-angiotensin system, hypertrophy and gene expression in cardiac myocytes. 1042 Mar 93

It has been proposed that the local renin-angiotensin system is activated in the adventitia after vascular injury. However, the physiological role of Angiotensin II (Ang II) in the adventitia has not been studied at a cellular level. This study was designed to assess the role of Ang II in the growth response of cultured adventitial fibroblasts (AFs). Adventitial explants of the rat thoracic aorta showed outgrowth of AFs within 5-7 days. Ang II caused hyperplastic response of AF cultures. The Ang II-induced mitogenic response of AFs was mediated primarily by the AT1 receptor. Ang II caused a rapid induction of immediate early genes (c-fos, c-myc and jun B). Induction of c-fos expression was fully blocked by an AT1 receptor antagonist but not by an AT2 receptor antagonist. Epidermal growth factor (EGF), platelet-derived growth factor-BB (PDGF-BB) and basic fibroblast growth factor (bFGF) induced DNA synthesis in AFs. Co-stimulation of AFs with the growth factors and Ang II potentiated the incorporation of 3H-thymidine into DNA. Results from this study indicate that Ang II causes mitogenesis of AFs via AT1 receptor stimulation and potentiates the responses to other mitogens. These data suggest that the Ang II may play an important role in regulating AF function during vascular remodeling following arterial injury.
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PMID:Angiotensin II stimulates proliferation of adventitial fibroblasts cultured from rat aortic explants. 1057 43

Vascular remodeling and rearrangement of the extracellular matrix formation are among the major adaptive mechanisms to chronic increase in blood pressure. In previous studies we have found that angiotensin II (Ang II) participates in the hypertension-associated aortic and renal vascular fibrosis by stimulating collagen type I formation. The purpose of the present study was to gain insight into the molecular events that lead from the Ang II receptor to collagen I gene activation. To this end, we used a novel strain of transgenic mice harboring the luciferase gene under the control of the collagen I-alpha(2) chain promoter [procolalpha(2)(I)]. Ang II produced an early (1 hour) 2- to 3-fold stimulation of procolalpha(2)(I) activity in freshly isolated aortas and renal cortical slices (P:<0. 01) followed by similar increase in procolalpha(2)(I) mRNA aortic levels. This effect of Ang II was inhibited by AT1-receptor antagonism (candesartan) and blockade of the MAPK/ERK cascade (PD98059); in contrast, inhibition of the P38 kinase pathway (SB202190) and blockade of the release of the transcription factor NFkappaB (PDTC) did not have any effect in the Ang II-induced activation of the collagen I gene. In addition, Ang II induced a rapid (5 minutes) increase of the MAPK/ERK activity that was accompanied by increased expression (3-fold) of the c-fos proto-oncogene. This increase of c-fos mRNA expression was blocked by PD98059; in addition, curcumin, a blocker of the transcriptional factor AP-1, canceled the effect of Ang II on the collagen I gene. Decorin, a scavenger of the active form of transforming growth factor-beta (TGF-beta), canceled the Ang II effect on collagen I gene, whereas inhibition of the MAPK/ERK pathway had no effect on the TGF-beta-induced activation of procolalpha(2)(I). These data indicate that the cellular events after AT1 receptor stimulation and leading to activation of collagen I gene expression require activation of both the MAPK/ERK and TGF-beta signaling pathways.
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PMID:Angiotensin II activates collagen I gene through a mechanism involving the MAP/ER kinase pathway. 1098 60

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