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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent evidence suggests that vasoconstrictive substances, including angiotensin II (Ang II), may function as a vascular smooth muscle growth promoting substance and may contribute to vascular hypertrophy in hypertension. Atrial natriuretic polypeptide (ANP) is known to be a physiological antagonist to Ang II in blood pressure and fluid homeostasis. Moreover, we have demonstrated that ANP can attenuate Ang II's action on vascular hypertrophy. In this study, we investigated the potential molecular mechanisms for the interaction of ANP and Ang II on vascular cell growth. Ang II dose-dependently induced RNA synthesis in post confluent cultured rat aortic smooth muscle (RASM) cells. ANP (10(-7) M) inhibited the hypertrophic effect of Ang II at the concentration of 10(-10) - 10(-8) M) but exerted no effect on the action of higher doses (10(-7) - 10(-6) M) of Ang II. Ang II (10(9) - 10(-8) M) and a protein kinase C activator, phorbol 12-myristate 13-acetate (PMA, 10(-8) M) rapidly induced c-fos as well as c-Jun and Jun-B mRNA expression in RASM cells. ANP (10(-7) M) itself had no apparent effect on the expression of these protooncogenes. Furthermore, ANP did not inhibit the induction of these protooncogenes by Ang II or PMA. Paradoxically, ANP (10(-7) M) significantly enhanced c-fos mRNA expression induced by Ang II and PMA. However, the chloramphenicol acetyl transferase (CAT) assay using a CAT expression vector containing the AP-1 binding element showed that ANP had no effect on the basal and PMA-stimulated AP-1 activity in transfected RASM cells. We conclude, therefore, that the inhibitory effect of ANP on the growth of vascular smooth muscle cells in vitro does not occur through the regulation of these protooncogene expressions.
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PMID:Interaction of atrial natriuretic polypeptide and angiotensin II on protooncogene expression and vascular cell growth. 182 53

The effects of intracerebroventricular (i.c.v.) injections of angiotensin II (Ang II) on the expression of inducible transcription factors (ITF) (c-Fos, FosB, c-Jun, JunB, JunD, Krox-20 and Krox-24) in the brain of conscious rats were assessed immunohistochemically using polyclonal antisera. Ang II (1, 10, 100 ng) induced after 90 min a dose-dependent expression of c-Fos, FosB, c-Jun, JunB and Krox-24, which was confined to four specific brain areas, namely the subfornical organ (SFO), median preoptic area (MnPO), paraventricular nucleus (PVN) and supraoptic nucleus (SON). In the above-mentioned regions, JunD exhibited a high basal staining which was not visibly altered by Ang II. Krox 20 was not induced by AnG II. FosB was only induced 4 h after i.c.v. injection of 100 ng Ang II in the MnPO and PVN. The Ang II-AT1 receptor antagonist, losartan, applied i.c.v. 5 min prior to Ang II (100 ng, i.c.v.) prevented the Ang II-induced ITF expression. In spontaneously hypertensive rats (SHR) but not in Wistar rats with nephrogenic hypertension due to aortic banding (WIab), the Ang II-induced expression of c-Fos, and c-Jun was enhanced in all four areas when compared to normotensive Wistar Kyoto (WKY)- and Wistar (WI) rats. The Ang II-induced expression of Krox-24 in the SFO, MnPO and PVN in SHR was also significantly increased when compared to WKY, WI and WIab rats. Our data demonstrate that a stimulation of periventricular Ang II-AT1 receptors induces a temporally and spatially highly differentiated expression pattern of ITFs restricted to four distinct regions of the forebrain involved in blood pressure regulation and body fluid homeostasis. The points to a strictly regulated expression of target genes in the respective regions. The enhanced Ang II-induced expression of ITFs in SHR compared to normotensive controls is not due to elevated blood pressure itself, since it was not observed in secondary hypertensive rats WIab. Thus, the increased sensitivity to Ang II in SHR appears to be genetically determined. The target genes regulated by Ang II-induced ITFs will have to be identified.
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PMID:Complex activation of inducible transcription factors in the brain of normotensive and spontaneously hypertensive rats following central angiotensin II administration. 889 87

A stimulated brain renin-angiotensin system has been implicated in genetic hypertension. We compared the effects of an intracerebroventricular injection of angiotensin II (100 ng) on the expression of inducible transcription factors c-Fos, c-Jun, and Krox-24 in the brain of spontaneously hypertensive rats (SHR). in Wistar rats with nephrogenic hypertension induced by aortic banding, and in normotensive Wistar-Kyoto and Wistar rats immunohistochemically. Generally, the angiotensin II-induced transcription factor expression was strictly confined to four distinct forebrain areas: the subfornical organ, median preoptic area, paraventricular nucleus, and supraoptic nucleus. In SHR, the angiotensin II-induced c-Fos and c-Jun expressions were significantly enhanced compared with those in normotensive control strains as well as in secondary hypertensive Wistar rats. Krox-24 expression in the subfornical organ, median preoptic area, and paraventricular nucleus of SHR was also significantly increased compared with that in all control strains. In the supraoptic nucleus, significant differences could be discriminated between SHR and secondary hypertensive Wistar rats. Injection of isotonic saline or arginine vasopressin (100 ng) as controls did not induce any expression of c-Fos, c-Jun, or Krox-24. Our findings demonstrate an enhanced sensitivity of SHR to angiotensin II-induced transcription factor expression in distinct brain areas involved in central blood pressure and osmotic control that is independent of blood pressure.
Hypertension 1997 Feb
PMID:Increased brain transcription factor expression by angiotensin in genetic hypertension. 904 Apr 44

We first examined the activities of extracellular signal-regulated kinases (ERKs) and c-Jun NH2-terminal kinases (JNKs) in the aorta of hypertensive rats. In Dahl salt-sensitive (DS) rats, chronic hypertension caused by a high-salt diet was followed by sustained activation of aortic p42ERK and p44ERK. p46JNK and p55JNK activities were also increased in hypertensive DS rats, but returned to control levels earlier than ERKs, suggesting that ERKs and JNKs may be independently activated in hypertensive rats. In stroke-prone spontaneously hypertensive rats (SHRSP) which spontaneously develop hypertension under a low salt-diet, aortic p42ERK and p44ERK activities were progressively increased with the development of hypertension, compared with control normotensive rats. p46JNK and p55JNK activities in SHRSP were increased, with a different time course from ERKs. Thus, we first demonstrated that ERKs and JNKs activities are chronically and differentially increased in the aorta of hypertensive rats, suggesting the involvement of these kinases in hypertensive vascular diseases.
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PMID:Extracellular signal-regulated kinase and c-Jun NH2-terminal kinase activities are continuously and differentially increased in aorta of hypertensive rats. 922 52

The upregulation of left ventricular (LV) atrial natriuretic peptide (ANP) mRNA is a highly conserved marker of cardiac hypertrophy. The aim of this study was to further examine the pathway leading to ANP induction during pressure overload of the heart. Systolic wall stress was imposed acutely on isovolumetrically beating rat hearts in a Langendorff apparatus (sigma-=300 x 10[3] dyne/cm2). Northern and Western blots revealed that elevated wall stress induced LV c-fos and c-jun mRNAs (3.5- and 3-fold, P<.05 after 60 minutes), c-Fos and c-Jun proteins (3.9- and 4.3-fold, P<.05 after 120 minutes), as well as ANP mRNA (2.2-fold, P<.05 after 120 minutes). ANP upregulation was prevented by inhibition of protein synthesis (cycloheximide). Electrophoresis mobility shift assays were performed to link c-Fos and c-Jun (ie, components of the heterodimeric transcription factor AP-1) and ANP induction. A putative AP-1 binding site within the rat ANP promoter (nucleotides -512 to -473) bound specifically to nuclear proteins of wall stress-stimulated hearts. Antibodies directed against c-Fos protein resulted in a shift of this DNA/protein complex, suggesting physical interaction between AP-1 and the ANP promoter. Myocardial transfection of promoter constructs revealed that after acute imposition of wall stress, this AP-1 site enhanced a reporter gene (8- to 10-fold compared with a minimal promoter, P<.05). Interestingly, nuclear extracts of stimulated hearts as well as pure AP-1 protein bound to a putative CRE site (nucleotides -613 to -584) as well. Like the AP-1 site, this cAMP-responsible element (CRE) site was found to enhance the transfected ANP promoter/reporter gene significantly (17.5-fold, P<.05). Mutation of either AP-1 or CRE sites did not decrease reporter gene activity, whereas mutation of both resulted in loss of inducibility. These experiments suggest that LV ANP regulation after acute wall stress includes the activation of AP-1 and/or CRE cis acting elements. However, the transient nature of c-fos and c-jun upregulation also suggests that AP-1 is not the only mediator of ANP induction in LV hypertrophy.
Hypertension 1997 Dec
PMID:Regulation of the rat atrial natriuretic peptide gene after acute imposition of left ventricular pressure overload. 940 52

To examine chronic changes in mitogen-activated protein (MAP) kinases in cardiac hypertrophy, we determined the activities of two subfamilies of MAP kinases, including extracellular signal-regulated kinases (ERKs) and c-Jun NH2-terminal kinases (JNKs), in the heart of stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto rats (WKY) aged 5, 8, 14, and 24 weeks. MAP kinases were determined by using in-gel kinase assay. In both the left and right ventricles of WKY, the activities of ERKs (p44ERK and p42ERK) and JNKs (p46JNK and p55JNK) decreased significantly with age, indicating that aging remarkably downregulated cardiac MAP kinase activities. In SHRSP, left ventricular ERK and JNK activities were already significantly higher at the mild hypertensive phase than they were in the same age of WKY, and they remained higher until development of left ventricular hypertrophy. On the contrary, the right ventricle of SHRSP, which did not exhibit cardiac hypertrophy, had no significant increase in ERK or JNK activities compared with WKY, except for the slight increase in p55JNK in 24-week-old SHRSP. Antihypertensive treatment of SHRSP with imidapril, an angiotensin-converting enzyme inhibitor, decreased the left ventricular JNK activities (P<.01) but did not affect ERK activities, suggesting the contribution of hypertension or the renin-angiotensin system to the increase in JNKs. Our observations provide the first evidence that both ERK and JNK activities are higher in the left ventricle of SHRSP than WKY. However, further study is needed to elucidate the mechanism and the significance of the increased cardiac MAP kinases in SHRSP.
Hypertension 1998 Jan
PMID:Cardiac mitogen-activated protein kinase activities are chronically increased in stroke-prone hypertensive rats. 944 90

The in vivo signal transduction pathway, responsible for hypertension-induced glomerular injury, remains to be clarified. In this study, the effect of angiotensin II (Ang II)-induced hypertension was examined on glomerular mitogen activated protein kinases (MAPK), including extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK), and on glomerular transcription factors activator protein-1 (AP-1) and Sp 1. MAPK activities were determined by in-gel kinase assay. DNA binding activity of AP-1 and Sp 1 was determined by gel mobility shift assay. Continuous infusion of Ang II (1000 ng/kg per min, intravenously) to conscious rats rapidly increased BP, followed by the rapid and transient activation of glomerular p42 and p44 ERK and p46 and p55 JNK with the peak at 15 to 180 min. Glomerular AP-1 binding activity was increased 2.6-fold (P < 0.01) at 24 h after the start of Ang II infusion. Supershift analysis showed that the activated AP-1 complexes contained c-Fos and c-Jun proteins. On the other hand, glomerular Sp 1 DNA binding activity was not changed throughout 7 d of Ang II infusion. These results provided the first in vivo evidence that Ang II-induced hypertension causes the activation of glomerular ERK and JNK, leading to the activation of AP-1. Thus, ERK and JNK signaling cascades, via the activation of AP-1, may be implicated in the development of hypertension-induced glomerular injury.
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PMID:Activation of glomerular mitogen-activated protein kinases in angiotensin II-mediated hypertension. 951 99

Progressive renal diseases lead to prolonged glomerular hypertension, which induces the proliferation of mesangial cells. This proliferation is thought to be involved in the development of renal injury. Here we investigate mitogen-activated protein kinase (MAPK) activation and cell proliferation in mesangial cells under conditions of high pressure. After pressure-load, the phosphorylation level of MAPK (at Tyr-204) increases rapidly with a peak at 1 min, although the amount of MAPK remains almost constant during pressure-load. To confirm the activation of MAPK, we carried out an immunoprecipitation-kinase assay. MAPK activity during pressure-load shows kinetics similar to that of the tyrosine phosphorylation. In contrast, c-Jun N-terminal kinase 1 (JNK1) phosphorylation falls below basal levels in response to high pressure. Immunocytochemical observations show phosphorylated MAPK in the nucleus at 10 min. The expression of c-Fos, a nuclear transcription factor, is induced by high pressure, and the induction is significantly inhibited by PD98059 (50 microM), an upstream MAPK/extracellular signal-regulated kinase kinase (MEK) inhibitor of MAPK. The expression of the c-Jun that is induced by JNK1 activation remains unchanged during pressure-load. MAPK phosphorylation and cell proliferation by applied pressure are significantly inhibited by genistein, a tyrosine kinase inhibitor in a dose-dependent manner, but not by protein kinase C inhibitors, chelerythrine and GF109203X. Genistein also blocks pressure-induced tyrosine phosphorylation of proteins with molecular masses of 35, 53, and 180 kDa. To clarify the physiological role in MAPK activation under high pressure conditions, we transfected antisense MAPK DNA into mesangial cells. The antisense DNA (2 microM) inhibited MAPK expression by 80% compared with expression in the presence of sense or scrambled DNA, and significantly blocked pressure-induced cell proliferation. Treatment of cells with MEK inhibitor also produced a similar result. MEK inhibitor strongly suppresses DNA synthesis induced by pressure-load. Cyclin D1 expression is significantly increased under high pressure conditions, and the increase is blocked by treatment with MEK inhibitor. These findings show that pressure-load, a novel activator of MAPK, induces the activation of tyrosine kinases, and enhances the proliferation of mesangial cells, probably through cyclin D1 expression.
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PMID:Applied pressure enhances cell proliferation through mitogen-activated protein kinase activation in mesangial cells. 964 52

Hypertension increases mechanical force on the arterial wall by as much as 30%, resulting in marked alterations in signal transductions and gene expression in vascular smooth muscle cells (VSMCs) that contribute to matrix protein synthesis, cell proliferation, and differentiation. How the mechanical stimuli are converted into a biological signal in cells has yet to be studied. We investigated the role of both cyclic strain and shear stresses in initiating the cellular signaling on cultured VSMCs and found that mechanical forces evoked activation of mitogen-activated protein kinases, followed by enhanced DNA binding activity of transcription factor AP-1. Physical forces rapidly induced phosphorylation of platelet-derived growth factor receptor (PDGFR) alpha, an activated state. When GRB2, an adapter protein, was immunoprecipitated from treated VSMCs followed by Western blot analysis with anti-phosphotyrosine, -PDGFR alpha, and -GRB2 antibodies, respectively, phosphotyrosine positive staining was observed on PDGFR alpha bands of the same blot in stretch-stressed VSMCs, supporting the mechanical stress-induced activation of PDGFR alpha. Conditioned medium from stretch-stressed VSMCs did not result in PDGFR alpha phosphorylation, and antibodies binding to all forms of PDGFs did not block stress-induced PDGFR alpha activation. Thus, mechanical stresses may directly perturb the cell surface or alter receptor conformation, thereby initiating signaling pathways normally used by growth factors.
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PMID:Activation of PDGF receptor alpha in vascular smooth muscle cells by mechanical stress. 973 16

Two subgroups of mitogen-activated protein kinases, c-jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), are thought to be involved in cultured cardiac myocyte hypertrophy and gene expression. To examine the in vivo activation of these kinases, we measured cardiac JNK and ERK activities in conscious rats subjected to acute or chronic angiotensin II (Ang II) infusion, by using in-gel kinase methods. About 50 mm Hg rise in blood pressure by Ang II (1000 ng . kg-1 . min-1) infusion caused larger activation of left ventricular JNK than ERK, via the AT1 receptor. In spite of short duration (about 30 minutes) of maximal blood pressure elevation by Ang II, JNK sustained the peak value (more than 5-fold increase) from 15 minutes up to at least 3 hours. Similar activation of JNK was seen in the right ventricle. Thus, cardiac JNK activation by Ang II seems to be in part mediated by its direct action via the AT1 receptor. The dose-response relationships for Ang II-induced rises in blood pressure and cardiac JNK and ERK activation indicated that cardiac JNK or ERK was not activated by a mild increase in blood pressure and that cardiac JNK was activated by Ang II-mediated hypertension in a more sensitive manner than ERK. Cardiac hypertrophy, induced by chronic Ang II infusion, was preceded by JNK activation without ERK activation. Furthermore, gel mobility shift analysis showed that cardiac JNK activation was followed by increased activator protein-1 DNA binding activity due to c-Fos and c-Jun. These results provided the first evidence for the preferential activation of cardiac JNK in Ang II-induced hypertension and suggested that JNK might play some role in Ang II-induced cardiac hypertrophic response in vivo. However, further study is needed to elucidate the role of JNK in cardiac hypertrophy in vivo.
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PMID:Differential activation of cardiac c-jun amino-terminal kinase and extracellular signal-regulated kinase in angiotensin II-mediated hypertension. 975 46


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