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

Mitogen-activated protein (MAP) kinase cascades are major signaling systems by which cells transduce extracellular cues into intracellular responses. In general, MAP kinases are activated by phosphorylation on tyrosine and threonine residues and inactivated by dephosphorylation. Therefore, MAP kinase phosphatase-1 (MKP-1), a dual-specificity protein tyrosine phosphatase that exhibits catalytic activity toward both regulatory sites on MAP kinases, is suggested to be responsible for the downregulation of extracellular signal-regulated kinase (ERK), stress-activated protein kinase (SAPK), and p38 MAP kinase. In the present study, we examined the role of these MAP kinases in the induction of MKP-1 in vascular smooth muscle cells (VSMCs). Extracellular stimuli such as platelet-derived growth factor (PDGF), 12-O-tetradecanoylphorbol 13-acetate (TPA), and angiotensin II, which activated ERK but not SAPK/p38 MAP kinase, induced a transient induction of MKP-1 mRNA and its intracellular protein. In addition, PD 098059, an antagonist of MEK (MAP kinase/ERK kinase), the upstream kinase of ERK, significantly reduced the PDGF-induced activation of ERK and potently inhibited the expression of MKP-1 after stimulation with PDGF, thereby demonstrating the induction of MKP-1 in response to activation of the ERK signaling cascade. Furthermore, anisomycin, a potent stimulus of SAPK and p38 MAP kinase, also induced MKP-1 mRNA expression. This effect of anisomycin was significantly inhibited in the presence of the p38 MAP kinase antagonist SB 203580. These data suggest the induction of MKP-1, not only after stimulation of the cell growth promoting ERK pathway but also in response to activation of stress-responsive MAP kinase signaling cascades. We suggest that this pattern of MKP-1 induction may be a negative feedback mechanism in the control of MAP kinase activity in VSMCs.
Hypertension 1998 Oct
PMID:Regulation of mitogen-activated protein kinase phosphatase-1 in vascular smooth muscle cells. 977 60

We previously showed that arginine vasopressin (AVP) stimulates heat shock protein 27 (HSP27) induction through protein kinase C activation in aortic smooth muscle A10 cells. In the present study, we examined whether the mitogen-activated protein (MAP) kinase superfamily is involved in the AVP-stimulated HSP27 induction in A10 cells. AVP stimulated the phosphorylation of p42/p44 MAP kinase and p38 MAP kinase. On the contrary, AVP had little effect on SAPK (stress-activated protein kinase)/JNK (c-Jun N-terminal kinase) phosphorylation. The HSP27 accumulation by AVP was not affected by PD98059, an inhibitor of the upstream kinase that activates p42/p44 MAP kinase. SB203580 and PD169316, specific inhibitors of p38 MAP kinase, suppressed the AVP-induced accumulation of HSP27. 12-O-tetradecanoylphorbol 13-acetate, an activator of protein kinase C, induced accumulation of HSP27 and was not inhibited by PD98059 but was inhibited by SB203580. Calphostin C and ET-18-OCH(3), inhibitors of protein kinase C, reduced the phosphorylation of p38 MAP kinase by AVP. SB203580 and PD169316 suppressed the AVP-increased levels in mRNA for HSP27. Dissociation of the aggregated HSP27 to the dissociated HSP27 was induced by AVP. These results strongly suggest that p38 MAP kinase takes part in the pathway of the AVP-stimulated induction of HSP27 in vascular smooth muscle cells.
Hypertension 2000 Feb
PMID:p38 MAP kinase is required for vasopressin-stimulated HSP27 induction in aortic smooth muscle cells. 1067 16

Mitogen-activated protein (MAP) kinases are important intracellular mediators for proliferation and hypertrophy and therefore may also regulate cardiomyoblast growth in hypertensive heart disease. Thus, the aim of the present study was to examine the activities of MAP kinases, namely extracellular signal-regulated kinase (ERK)1,2, c-Jun NH2-terminal kinases (JNK)1,2 and p38 MAP kinase, in myocardial tissue of 12-week-old Prague normotensive (PNR) and hypertensive rats (PHR), a model of genetic hypertension with marked cardiac hypertrophy. Systolic blood pressure was 121 +/- 5 in PNR and 208 +/- 15 mm Hg in PHR (p < 0.01). Total heart weight was 247 +/- 4 in PNR vs. 316 +/- 4 mg/100 g body weight in PHR (p < 0.01). Left and right ventricular weights were 121 +/- 5 and 53 +/- 3 in PNR vs. 168 +/- 4 (p < 0.01) and 57 +/- 2 mg/100 g body weight (n.s.) in PHR. Using anti-ERK2 Western blot analysis as well as immunocomplex ERK activity assay, we found no activation of ERK2 in left or right ventricular tissue of PHR and PNR. Similary, p38 MAP kinase phosphorylation and activity were not detectable. In contrast, Western blot analysis using antiphospho-JNK antibodies revealed in myocardial tissue of right and left ventricles significantly greater phosphorylation of JNK2 in PHR than in PNR. This finding was confirmed by immunocomplex JNK activity assay using ATF-2 as substrate, which demonstrated a significant increase in JNK activity in the left ventricle of PHR as compared to PNR (6.4 +/- 1.5 vs. 2.5 +/- 0.5 OD; each n = 5; p < 0.05). In conclusion, cardiac JNK2 seems to be regulated differently from ERK2 in this rat model. In PHR, as compared to PNR, we found enhanced activity of JNK2 in the left and right ventricles suggesting that JNK2 is involved in hypertensive cardiac disease. The rise in JNK in both ventricles may result indirectly from humoral stimuli, e.g., endothelin-1 and/or angiotensin II, and may contribute to ventricular hypertrophy in this model of spontaneous hypertension.
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PMID:Cardiac hypertrophy in the Prague-hypertensive rat is associated with enhanced JNK2 but not ERK tissue activity. 1117 7

Vascular remodeling in hypertension is associated with cell growth and increased deposition of extracellular matrix components, particularly collagen. Mechanisms underlying these processes are unclear, but MAP kinases, particularly ERK1/2 and p38 MAP kinase, may be important. We studied the role of ERK1/2 and p38 MAP kinase in vascular smooth muscle cell (VSMC) collagen synthesis and growth mediated by angiotensin (Ang) II in spontaneously hypertensive rats (SHR). Cultured mesenteric VSMC from Wistar-Kyoto rats and SHR were used. Phosphorylation of ERK1/2 and p38 MAP kinase were assessed by Western blots with phosphospecific antibodies. Ang II-stimulated DNA and collagen synthesis were determined by measuring incorporation of (3)H-thymidine and (3)H-proline, respectively. mRNA expression of procollagen I and III was determined by reverse transcription-polymerase chain reaction. Ang II increased ERK1/2 and p38 MAP kinase phosphorylation. Responses were augmented in SHR. Effects were inhibited by irbesartan, a selective AT(1) antagonist, but not by PD123319, a selective AT(2) blocker. Ang II stimulated (3)H-thymidine and (3)H-proline incorporation. These actions were enhanced 2- to 3-fold in SHR. PD98059, selective inhibitor of the ERK1/2 pathway, attenuated Ang II-induced growth and collagen effects and normalized responses in SHR. SB212190, a selective p38 MAP kinase inhibitor, did not alter Ang II-elicited DNA synthesis but reduced collagen production and mRNA expression of procollagen I and III in SHR. These data demonstrate that (1) Ang II-mediated activation of p38 and ERK1/2 is increased in SHR, (2) augmented growth responses are generated by ERK1/2-dependent, p38 MAP kinase-independent pathways, and (3) p38 MAP kinase influences Ang II-induced collagen production in SHR but not in Wistar-Kyoto rats. These results indicate differential roles of ERK1/2 and p38 MAP kinase in AT(1)-stimulated VSMC growth and collagen production, which may contribute to vascular remodeling in hypertension.
Hypertension 2001 Feb
PMID:p38 Map kinase regulates vascular smooth muscle cell collagen synthesis by angiotensin II in SHR but not in WKY. 1123 Mar 37

The function of vascular endothelium as a biomechanical sensor permits alterations in gene expression in the vascular tree in response to wall stress. The present study explored the mechanism by which the arterial endothelium responds to changes in dietary salt. Normotensive rats were fed diets containing varying amounts of NaCl for 4 days. At that time, levels of phosphorylated p38 MAP kinase, p42/44 MAP kinase, and p46/54 JNK/SAP kinase increased when the diet contained > or = 3.0% NaCl. Kinase assays demonstrated dose-response relationships between dietary salt intake and the activities of p38 MAP kinase and p42/44 MAP kinase. Aortic segments from animals on the 8.0% NaCl diet produced greater amounts of total and active transforming growth factor-beta 1 (TGF-beta1) and nitric oxide. The MEK1 inhibitor, PD-098059, and the p38 MAP kinase inhibitor, SB-203580, decreased production of these bioactive compounds to background levels. Intravenous injection of tetraethylammonium chloride (TEA) into rats on the 8.0% NaCl diet decreased the activities of p38 MAP kinase and p42/44 MAP kinase, compared with rats on the same diet and given vehicle intravenously. These findings provided direct evidence that dietary salt modulated gene expression in the arterial wall through a tetraethylammonium-sensitive mechanism and activation of the p38 and p42/44 MAP kinase pathways.
Hypertension 2002 Feb
PMID:Increased dietary salt activates rat aortic endothelium. 1184 91

Cardiac fibrosis results from proliferation of interstitial fibroblasts and concomitant increased biosynthesis of extracellular matrix (ECM) components and is often complicated by cardiac hypertrophy. This study was conducted to investigate whether norepinephrine (NE) potentiates transforming growth factor-beta (TGF-beta)-induced cardiac fibrosis. The expression of the cardiac ECM proteins, plasminogen activator inhibitor-1 (PAI-1), fibronectin, and collagen type I, was examined by Western blotting using extracts from neonatal rat primary cardiac fibroblasts. In cardiac fibroblasts, treatment with a combination of NE and TGF-beta1 increased cell proliferation and ECM expression. Luciferase assays were conducted to clarify the effect of NE on TGF-beta signaling. TGF-beta1 (1 ng/mL) increased the specific signaling activity 2-fold, whereas the combination of NE (10 micro mol/L) and TGF-beta1 (1 ng/mL) resulted in an approximate 10-fold increase in specific signaling activity. We confirmed that treatment with NE markedly enhances TGF-beta-induced phosphorylation of activating transcription factor 2 (ATF-2). These results indicated that NE has a synergistic effect on TGF-beta signaling. To determine whether this activation by NE was mediated by the TGF-beta1 receptor, we used a dominant negative vector of the TGF-beta1 type II receptor, and the synergistic effects were inhibited. Furthermore, this synergistic effect was attenuated by a specific inhibitor of p38, SB203680. These data indicate that NE enhances cardiac fibrosis through TGF-beta1 post-receptor signaling, predominantly via the p38 MAP kinase pathway.
Hypertension 2002 Aug
PMID:Norepinephrine enhances fibrosis mediated by TGF-beta in cardiac fibroblasts. 1215 5

In adult mammalian kidney, cyclooxygenase-2 (COX-2) expression is found in restricted subpopulations of cells. High levels of expression can be detected in the macula densa (MD) and associated cortical thick ascending limb of Henle (cTALH) cells and medullary interstitial cells (MICs). In human biopsy specimens, COX-2 expression is also detected in glomerular podocytes and increased podocyte expression is seen in experimental models of progressive glomerular injury. Physiological regulation of COX-2 in these cellular compartments suggests functional roles for eicosanoid products of the enzyme. COX-2 expression increases in high-renin states (salt restriction, angiotensin-converting enzyme inhibition, renovascular hypertension) and selective COX-2 inhibitors significantly decrease plasma renin levels, renal renin activity and mRNA expression. There is evidence for negative regulation of MD/cTALH COX-2 by angiotensin II and by glucocorticoids and mineralocorticoids. Conversely, nitric oxide (NO) generated by neuronal nitric oxide synthase (nNOS) is a positive modulator of COX-2 expression. Decreased extracellular chloride increases COX-2 expression in cultured cTALH, an effect mediated by increased p38 MAP kinase activity and, in vivo, a sodium-deficient diet increases expression of activated p38 in MD/cTALH. In contrast to COX-2 in MD/cTALH, COX-2 expression in MICs increases in response to a high-salt diet, as well as water deprivation. Studies in cultured MICs confirm that expression is increased in response to hypertonicity, and expression is mediated at least in part by nuclear factor-kappaB (NFkappaB) activation. COX-2 inhibition leads to apoptosis of MICs in response to hypertonicity in vitro and following water deprivation in vivo. In addition, COX-2 metabolites appear to be important mediators of medullary blood flow and renal salt handling. Therefore, there is increasing evidence that COX-2 is an important physiological mediator of kidney function.
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PMID:Cyclooxygenase-2 and the kidney: functional and pathophysiological implications. 1268 21

17beta-estradiol reduces myocardial hypertrophy and left ventricular mass, suggesting that the selective estrogen receptor modulator raloxifene may have similar effects. However, it is not clear whether raloxifene inhibits both cardiac hypertrophy and dysfunction. We used transverse aortic-banded mice to produce pressure-overload cardiac hypertrophy and used neonatal rat ventricular cardiomyocytes to investigate the cellular mechanisms of raloxifene on cardiac hypertrophy. Left ventricular mass and fractional shortening of mice hearts were measured by transthoracic echocardiography. Protein synthesis of cardiomyocytes was evaluated by incorporation of [3H]leucine into cardiomyocytes exposed to angiotensin II. Phosphorylation of mitogen-activated protein (MAP) kinase was also observed in cardiomyocytes. Raloxifene prevented increases in left ventricular mass and decreases of fractional shortening at 4 weeks after aortic banding. Pretreatment with raloxifene before angiotensin II stimulation inhibited the increase in [3H]leucine incorporation into neonatal rat cardiomyocytes in a concentration-dependent manner. This inhibition was partially but not significantly attenuated by N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, and completely abolished by ICI182780, an estrogen receptor antagonist. Although the phosphorylation of p38 MAP kinase, c-Jun N-terminal kinase (JNK), or extracellular signal-regulated protein kinase (ERK) in cardiomyocytes was significantly increased by angiotensin II stimulation as compared with the control, pretreatment with raloxifene attenuated p38 MAP kinase phosphorylation, but neither JNK nor ERK phosphorylation. We conclude that raloxifene inhibits cardiac hypertrophy and dysfunction and that the inhibition of p38 MAP kinase phosphorylation after the stimulation of estrogen receptors may be involved in the cellular mechanisms of this agent.
Hypertension 2004 Feb
PMID:Raloxifene prevents cardiac hypertrophy and dysfunction in pressure-overloaded mice. 1467 19

The hypertrophy of vascular smooth muscle cells (VSMCs) is critical in vascular remodeling associated with hypertension, atherosclerosis, and restenosis. Recently, leptin has appeared to play a pivotal role in vascular remodeling. However, the mechanism by which leptin induces hypertrophy in vascular smooth muscle cells is still unknown. We studied the role of leptin as a potential hypertrophic factor in rat VSMCs. In the present study, leptin significantly increased [(3)H]leucine incorporation and the total protein/DNA ratio in VSMCs. The maximal hypertrophic effect was at 100ng/ml of leptin. Leptin induced phosphorylation and activation of p38 mitogen-activated protein (p38 MAP) kinase and of signal transducers and activators of transcription 3 in a concentration- and time-dependent manner. A p38 MAP kinase inhibitor SB203580 significantly inhibited leptin-induced hypertrophy, AG490 (a JAK2 inhibitor) partially inhibited it, and other MAP kinase inhibitors, PD98059 (an ERK inhibitor) and SP600125 (a JNK inhibitor), had no effect. These results indicate that leptin directly stimulates cellular hypertrophy via p38 MAP kinase in rat VSMCs.
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PMID:Leptin induces hypertrophy via p38 mitogen-activated protein kinase in rat vascular smooth muscle cells. 1572 Dec 67

Myogenic tone (MT), a fundamental stretch-sensitive vasoconstrictor property of resistance arteries and veins, is a key determinant of local blood flow regulation. We evaluated the pathways involved in MT development. The role of the RhoA/Rho kinase, p38 MAP kinase, and HSP27 in MT was investigated in the rabbit facial vein (RFV), previously shown to possess MT at a pressure level equivalent to 20 mm Hg. Venous MT is poorly understood, although venous diseases affect a large proportion of the population. Stretched RFV are characterized by a temperature-sensitive MT, which is normal at 39 degrees C but fails to develop at 33 degrees C. This allows for the discrimination of the pathways involved in MT from the multiple pathways activated by stretch. Isolated RFV segments were mounted in organ baths and stretched. Temperature was then set at 33 degrees C or 39 degrees C. MT was associated to the translocation of RhoA to the plasma membrane and the Rho kinase inhibitor Y27632 decreased stretch-induced MT by 93.1+/-4.9%. MT was also associated to an increase in p38 (131.0+/-12.5% at 39 degrees C versus 100% at 33 degrees C) and HSP27 phosphorylation (196.1+/-13.3% versus 100%), and the p38 MAP kinase inhibitor SB203580 decreased MT by 36.5+/-8.1%. (39 degrees C, compared with RFV stretched at 33 degrees C). Finally, phosphorylation of p38 was blocked by Y27632 and HSP27 phosphorylation was inhibited by SB203580 and Y27632. Thus, MT and the associated p38 and HSP27 phosphorylation seem to depend on RhoA/Rho kinase activation in stretch RFV.
Hypertension 2005 May
PMID:Involvement of RhoA/Rho kinase pathway in myogenic tone in the rabbit facial vein. 1583 33


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