Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclosporine A (CsA)-induced hypertension appears to be caused in part by neurogenic vasoconstriction, but the mechanism by which CsA activates the sympathetic nervous system is unknown. In T lymphocytes, the cellular target of CsA and the macrolide immunosuppressant FK506 (as complexes with their endogenous cytoplasmic receptors, or immunophilins) is the Ca(2+)-calmodulin-dependent phosphatase calcineurin. The presence of calcineurin and its colocalization with immunophilin in the brain led us to hypothesize that the phosphatase also mediates CsA-induced sympathetic activation. We now report that sympathetic activity and arterial pressure in rats are increased not only by CsA but also by FK506, which is structurally unrelated to CsA but inhibits the same calcineurin-sensitive T-cell signaling pathway. In contrast, sympathetic activity and blood pressure are not increased by rapamycin, which forms an immunophilin complex that does not bind calcineurin. Furthermore, CsA- and FK506-induced sympathetic activation is attenuated for drug analogues possessing modest changes in molecular structure in a way that closely parallels the ability of each analogue to inhibit calcineurin-mediated T-cell signaling. These results implicate an important role for extralymphoid (ie, neuronal) calcineurin in mediating immunosuppressive drug toxicity.
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PMID:Cyclosporine- and FK506-induced sympathetic activation correlates with calcineurin-mediated inhibition of T-cell signaling. 768 70

Acute hypertension, induced in rats by intravenous injection of angiotensin II, previously has been shown to increase cerebrovascular permeability to macromolecules. The purpose of this study was to examine the effect of acute hypertension on Na+,K(+)-ATPase, the enzyme responsible for controlling ionic permeability of the cerebromicrovascular endothelium. The K(+)-dependent p-nitrophenylphosphatase activity of the cerebromicrovascular Na+,K(+)-ATPase was determined using microvessels prepared from hypertensive and normotensive rats. When compared to controls, a 70% decrease (P < 0.02) in the maximum rate (Vmax) of the Na+,K(+)-ATPase from hypertensive rats was evident with no change in the Michaelis constant (KM). In contrast, gamma-glutamyltranspeptidase, a marker enzyme for cerebral endothelial cells, was not significantly affected. Sodium arachidonate (1-100 microM) inhibited the phosphatase activity of the Na+,K(+)-ATPase in microvessels isolated from both normotensive and hypertensive rats in a dose-dependent manner. Furthermore, poly-unsaturated fatty acids (sodium linoleate and arachidonate) evoked the greatest inhibition of the enzyme, while sodium oleate and sodium palmitate inhibited the Na+,K(+)-ATPase to lesser extents. This regulation of enzyme activity by fatty acids was comparable in control and hypertensive groups. In summary, the data indicate that the cerebromicrovascular Na+,K(+)-ATPase was altered as a consequence of acute hypertension and that poly-unsaturated fatty acids can modulate this enzyme in microvessels derived from hypertensive or control rats.
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PMID:Alterations of cerebromicrovascular Na+,K(+)-ATPase activity due to fatty acids and acute hypertension. 809 29

This article reviews the current state of knowledge concerning cyclosporine A-induced hypertension after heart transplantation, its pathophysiology and management. The hypothesis is presented that a common molecular mechanism mediates both the immunosuppressive and the hypertensive actions of cyclosporine. The calcium-calmodulin dependent phosphatase, calcineurin, is the common cellular target mediating the salient immunosuppressive effects of both cyclosporine A and FK506. Calcineurin is even more plentiful in nonlymphoid tissues such as the nervous system, muscle, and kidney. Because these are the main target sites for cyclosporine A-induced toxicity, it has been hypothesized recently that inhibition of calcineurin mediates cyclosporine A-induced toxicity. This hypothesis is supported by increasing experimental evidence, at both the whole animal and cellular levels, indicating that the toxicity profile of cyclosporine A is duplicated by FK506 but not by rapamycin, a structural analog of FK506 which is a potent immunosuppressive agent but has no effect on calcineurin. Recent multicenter trials demonstrate that in the clinical setting the hypertensive and other side effects of cyclosporine A are duplicated by FK506. The clinical toxicity of rapamycin is as yet unknown.
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PMID:Hypertension after cardiac transplantation: pathophysiology and management. 856 50

The S phase-specific expression of histone genes provides an interesting model for studying activation of gene transcription during the cell cycle. In plants, however, trans-acting factors responsible for histone gene transcription are poorly documented. Using combined gel shift, UV cross-linking and competition analysis, we carried out a systematic study to identify and characterize proteins binding with the previously established cis elements of the plant histone gene promoters. Nuclear extracts prepared from the highly synchronizable tobacco BY2 cells were used. We confirmed the presence of proteins binding to the hexamer (ACGTCA) motif which has been previously identified as the binding site of wheat HBP-1 proteins. Interestingly, multiple proteins were found to bind specifically with the nonamer (CAATCCAAC) element and their DNA-binding activity was abolished upon in vitro protein phosphatase treatment. This later result imply phosphorylation/dephosphorylation as a potential post-translational control for DNA-binding activity of nonamer-binding proteins. In addition, the DNA-binding activity of these nonamer-binding proteins was found to be positively correlated with the S phase-specific expression of the histone genes in the synchronized cells, suggesting their function in the activation of transcription during the G1/S transition. Finally, several proteins were observed to bind specifically with an A/T-rich hexamer (TAATAT) motif. Their DNA-binding activity, however, was insensitive to phosphatase activity in vitro and relatively constitutive during the cell cycle. This A/T-rich hexamer as a new cis-acting element of plant histone genes is discussed.
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PMID:Protein complexes binding to cis elements of the plant histone gene promoters: multiplicity, phosphorylation and cell cycle alteration. 904 59

Recently, we demonstrated that elevated blood pressure activates mitogen-activated protein (MAP) kinases in rat aorta. Here we provide evidence that the vascular response to acute hypertension also includes induction of MAP kinase phosphatase-1 (MKP-1), which has been shown to function in the dephosphorylation and inactivation of MAP kinases. Restraint or immobilization stress, which leads to a rapid rise in blood pressure, resulted in a rapid and transient induction of MKP-1 mRNA followed by elevated MKP-1 protein expression in rat aorta. That the induction of MKP-1 by restraint was due to the rise in blood pressure was supported by the finding that several different hypertensive agents (phenylephrine, vasopressin, and angiotensin II) were likewise capable of eliciting the response, and sodium nitroprusside, a nonspecific vasodilator agent that prevented the acute rise in blood pressure in response to the hypertensive agents, abrogated MKP-1 mRNA induction. The in vivo effects could not be mimicked by treatment of cultured aortic smooth muscle cells with similar doses of the hypertensive agents. These findings support a role for MKP-1 in the in vivo regulation of MAP kinase activity during hemodynamic stress.
Hypertension 1997 Jul
PMID:Induction of mitogen-activated protein kinase phosphatase-1 during acute hypertension. 923 29

Smooth muscle contraction is the basis of the physiological reactivity of several systems (vascular, respiratory, gastrointestinal, urogenital ...). Hyperresponsiveness of smooth muscle may also contribute to a variety of problems such as arterial hypertension, asthma and spontaneous abortion. An increase in cytoplasmic calcium concentration ([Ca2+]i) is the key event in excitation-contraction coupling in smooth muscle and the relationship linking the [Ca2+]i value to the force of contraction represents the calcium sensitivity of the contractile apparatus (CaSCA). Recently, it has become evident that CaSCA can be modified upon the action of agonists or drugs as well as in some pathophysiological situations. Such modifications induce, at a fixed [Ca2+]i value, either an increase (referred to as sensitization) or a decrease (desensitization) of the contraction force. The molecular mechanisms underlying this modulation are not yet fully elucidated. Nevertheless, recent studies have identified sites of regulation of the actomyosin interaction in smooth muscle. Sensitization primarily results from the inhibition of myosin light chain phosphatase (MLCP) by intracellular messengers such as arachidonic acid or protein kinase C. In addition, phosphorylation of thin filament-associated proteins, caldesmon and calponin, increases CaSCA. Activation of small (monomeric) G-proteins such as rho or ras is also involved. Desensitization occurs as a consequence of phosphorylation of myosin light chain kinase (MLCK) by the calcium-calmodulin activated protein kinase II, or stimulation of MLCP by cyclic GMP-activated protein kinase. In the present review, examples of physiological modulation of CaCSA as well as pharmacological and pathophysiological implications are illustrated for some smooth muscles.
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PMID:Modulation of the calcium sensitivity of the smooth muscle contractile apparatus: molecular mechanisms, pharmacological and pathophysiological implications. 926 58

Trapidil, an antiplatelet drug, has been shown to reduce restenosis after angioplasty. It exerts its action, at least in part, by inhibiting vascular smooth muscle cell proliferation, antagonizing platelet-derived growth factor (PDGF). We examined its site of action on PDGF cellular signaling. Exposure of cultured rat vascular smooth muscle cells to increasing concentrations of trapidil for 18 hours resulted in a dose-dependent reduction in PDGF-BB-stimulated [3H] thymidine incorporation. Trapidil (400 microg/mL) increased PDGF beta-receptor protein by 28+/-8%, whereas PDGF-induced tyrosine phosphorylation of PDGF beta-receptor remained unchanged. PDGF-induced tyrosine phosphorylation of phospholipase Cgamma, the p85 regulatory subunit of phosphatidyl-inositol 3 kinase, Ras GTPase-activating protein, and an adaptor molecule Shc were also not altered. On the other hand, trapidil inhibited PDGF-stimulated mitogen-activated protein kinase (MAP kinase) activity by 35+/-7% at 10 minutes and by 32+/-10% at 6 hours. Activation of Raf-1, an upstream activator of MAP kinase, by PDGF was also attenuated by trapidil. Moreover, protein content of MAP kinase phosphatase-1, which inactivates MAP kinase, was elevated in trapidil-treated cells. These actions of trapidil may be mediated by cAMP. Thus, there was a 1.9-fold increase in cellular cAMP generation in trapidil-treated cells. The present results demonstrate that trapidil antagonizes PDGF-induced mitogenesis and MAP kinase activation in vascular smooth muscle cells, probably through cAMP.
Hypertension 1998 Feb
PMID:Trapidil inhibits platelet-derived growth factor-stimulated mitogen-activated protein kinase cascade. 946 Dec 38

The activation of mitogen-activated protein (MAP) kinase and increase in intracellular free calcium concentration ([Ca2+]i) are discussed in reference to activation of different protein kinases and growth of vascular smooth muscle cells (VSMCs). The aim of the present study was to investigate the role of angiotensin (Ang) II-induced increase in [Ca2+]i for activation of 44-kD/42-kD MAP kinase (p44mapk/p42mapk) and DNA synthesis in VSMCs. Experiments were performed by chelation of [Ca2+]i by the intracellular chelator 1,2-bis-(o-amino-5-methylphenoxy)ethane-N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester (MAPTAM). Ca2+ was measured by the fura 2 method. MAP kinase activation was determined by the Western blotting method. DNA synthesis was determined by measurement of [3H]thymidine incorporation into the cell DNA. Treatment of VSMCs with 20 micromol/L MAPTAM for 30 minutes resulted in a complete abolishment of the maximal Ang II-induced increase at 10 seconds. Ang II phosphorylated the p44mapk/p42mapk in a time-dependent manner, showing a maximum at 3 minutes. In MAPTAM-treated cells, the maximal phosphorylation of MAP kinase isoforms was shifted to 5 minutes, and dephosphorylation was delayed compared with untreated cells. In concordance with this finding, the induction of the MAP kinase phosphatase-1 was markedly impaired in MAPTAM-treated cells. Ang II induced a 2.3-fold increase in [3H]thymidine incorporation into DNA synthesis in untreated cells. This effect was not reduced in MAPTAM-treated cells. Treatment of the cells with PD 98059 (10 micromol/L), a MAP kinase kinase inhibitor, caused 85% inhibition of the Ang II-induced activation of MAP kinases but did not inhibit the Ang II-induced DNA synthesis. In conclusion, the Ang II-induced stimulation of the MAP kinase is a Ca2+-dependent process. Furthermore, blockade of the Ang II-induced stimulation of the early intracellular events, such as increase in [Ca2+]i or phosphorylation of the MAP kinase, is not accompanied by an inhibition of the Ang II-induced DNA synthesis.
Hypertension 1998 May
PMID:Role of mitogen-activated protein kinase in the angiotensin II-induced DNA synthesis in vascular smooth muscle cells. 957 28

Hyperinsulinemia (HI) and insulin resistance (IR) are frequently associated with hypertension and atherosclerosis. However, the exact roles of HI and IR in the development of hypertension are unclear. Mitogen-activated protein kinases (MAPK) are well-characterized intracellular mediators of cell proliferation. In this study, we examined the contribution of MAPK pathway in insulin-stimulated mitogenesis using primary vascular smooth muscle cells (VSMCs) isolated from aortas of normotensive Wistar-Kyoto rats (WKY) and spontaneous hypertensive rats (SHR). VSMCs were grown to confluence in culture, serum starved, and examined for DNA synthesis (using [3H]thymidine (TDR), immunoprecipitated MAPK activity, and MAPK phosphatase (MKP-1) induction). Basal rate of TDR incorporation into DNA was twofold higher in SHR compared with WKY (P < 0.005). Insulin caused a dose-dependent increase in TDR incorporation (150% over basal levels with 100 nM in 12 h). Stimulation was sustained for 24 h with a decline toward basal in 36 h. Pretreatment with insulin-like growth factor I (IGF-I) receptor antibody did not abolish mitogenesis mediated by 10-100 nM insulin, suggesting that insulin effect is mediated via its own receptors. Insulin had a small mitogenic effect in WKY (33% over basal). Insulin-stimulated mitogenesis was accompanied by a dose-dependent increase in MAPK activity in SHR, with a peak activation (>2-fold over basal) between 5 and 10 min with 100 nM insulin. Insulin had very small effects on MAPK activity in WKY. In contrast, serum-stimulated MAPK activation was comparable in WKY and SHR. Pretreatment with MEK inhibitor, PD-98059, completely blocked insulin's effect on MAPK activation and mitogenesis. Inhibition of phosphatidylinositol 3-kinase with wortmannin also prevented insulin's effects on MAPK activation and mitogenesis. In WKY, insulin and IGF-I treatment resulted in a rapid induction of MKP-1, the dual-specificity MAPK phosphatase. In contrast, VSMCs from SHR were resistant to insulin with respect to MPK-1 expression. We conclude that insulin is mitogenic in SHR, and the effect appears to be mediated by sustained MAPK activation due to impaired insulin-mediated MKP-1 mRNA expression, which may act as an inhibitory feedback loop in attenuating MAPK signaling.
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PMID:Vascular smooth muscle cell growth and insulin regulation of mitogen-activated protein kinase in hypertension. 968 33

Abnormal smooth muscle contraction may contribute to diseases such as asthma and hypertension. Alterations to myosin light chain kinase or phosphatase change the phosphorylation level of the 20-kDa myosin regulatory light chain (MRLC), increasing Ca2+ sensitivity and basal tone. One Rho family GTPase-dependent kinase, Rho-associated kinase (ROK or p160(ROCK)) can induce Ca2+-independent contraction of Triton-skinned smooth muscle by phosphorylating MRLC and/or myosin light chain phosphatase. We show that another Rho family GTPase-dependent kinase, p21-activated protein kinase (PAK), induces Triton-skinned smooth muscle contracts independently of calcium to 62 +/- 12% (n = 10) of the value observed in presence of calcium. Remarkably, PAK and ROK use different molecular mechanisms to achieve the Ca2+-independent contraction. Like ROK and myosin light chain kinase, PAK phosphorylates MRLC at serine 19 in vitro. However, PAK-induced contraction correlates with enhanced phosphorylation of caldesmon and desmin but not MRLC. The level of MRLC phosphorylation remains similar to that in relaxed muscle fibers (absence of GST-mPAK3 and calcium) even as the force induced by GST-mPAK3 increases from 26 to 70%. Thus, PAK uncouples force generation from MRLC phosphorylation. These data support a model of PAK-induced contraction in which myosin phosphorylation is at least complemented through regulation of thin filament proteins. Because ROK and PAK homologues are present in smooth muscle, they may work in parallel to regulate smooth muscle contraction.
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PMID:Different molecular mechanisms for Rho family GTPase-dependent, Ca2+-independent contraction of smooth muscle. 972 79


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