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

Evidence has been provided that the immunological mechanism is involved in the genesis or maintenance of hypertension. In the present study, we investigated the effects of interferon gamma, a potent immunomodulator derived from lymphocytes, on hypertension and organ damage in Dahl salt-sensitive rats and in spontaneously hypertensive rats. Subcutaneous injection of interferon gamma (5 x 10(4) units/kg body wt once a week for 10 weeks) reduced blood pressure in Dahl salt-sensitive rats fed a 4% high salt diet (174 versus 194 mm Hg, p less than 0.025). This blood pressure reduction was associated with an improvement of renal functions, an increase in glomerular filtration rate (690 versus 569 ml/day/100 g body wt, p less than 0.05), and decreases in urinary protein excretion (48 versus 78 mg/day/100 g body wt, p less than 0.025) and urinary N-acetyl-beta-D-glucosaminidase excretion (143 versus 183 milliunits/day/100 g body wt, p less than 0.05). Morphological investigation showed a marked resolution of the vascular injuries seen in untreated Dahl salt-sensitive rats, e.g., intimal and medial hyperplasia, with infiltration of inflammatory cells, and significant amelioration of the glomerular sclerotic changes. In contrast, interferon gamma affected neither blood pressure nor renal functions in spontaneously hypertensive rats. These data indicate that interferon gamma ameliorates the development of hypertension and vascular and renal injuries in Dahl salt-sensitive rats. The resolution of vascular and renal injuries contributes, in part, to the antihypertensive action of interferon gamma.
Hypertension 1992 Jun
PMID:Interferon gamma attenuates hypertensive renal injury in salt-sensitive Dahl rats. 159 85

While the roles of the platelet-derived growth factors (PDGFs) in vascular smooth muscle cells (SMCs) continue to be elucidated, these cells, especially in their activated 'synthetic' state, have also been found to express, and proliferate in response to, many of the other families of polypeptide growth factors, such as the fibroblast growth factors. Other stimulators of DNA synthesis, and particularly of SMC hypertrophy, include the vasoconstrictor hormones such as angiotensin II, as well as physical forces, especially stretch or tension. For many of these ligands, multiple receptors have been identified and their means of signal transduction are being characterized rapidly. Regulatory regions of these genes are being identified as are transcription factors. Complex post-transcriptional regulation has also been shown by the findings that some growth factors are phosphorylated, or translocated to the nucleus or the extracellular matrix. Inhibitors have also been identified. These include some prostaglandins, calcium antagonists, agonists that activate guanylate and adenylate cyclases, inhibitors of angiotensin-converting enzyme, interferon gamma, and heparin. Future studies are likely to show that tyrosine phosphatases and recessive oncogenes also regulate growth. The existence of so many autocrine/paracrine mitogens--together with some experimental data--suggests some redundancy in the system as well as some additive effects. Redundancy may limit the efficacy of antibodies to a single growth factor to block cell proliferation. Their evolutionary conservation implies some unique roles for each growth factor but these have not been apparent from in vitro studies to date. Further insights are apt to come from the increasing recognition that growth factors have other effects--on cell attachment, migration, survival, production of extracellular matrix, thrombosis, vaso-constriction, regulation of cytokine synthesis, and inhibition of growth. Many of these effects may prove to be context-dependent, as with the case of growth inhibition by transforming growth factor-beta. Studies in monolayer cultures may not obtain the same results as studies using cocultures of endothelial and smooth muscle cells, or 3-dimensional matrix cultures, organ cultures, or in the intact animal. In vivo descriptive studies of growth factors expressed in vascular embryogenesis, hypertension, atherosclerosis, acute balloon injury and thrombosis are being supplemented by interventions such as infusions with growth factors, antibodies, and toxin conjugates. These studies, and studies using transgenic mice and homologous recombination, should yield information as to mechanisms and may also suggest new therapies.
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PMID:Smooth muscle cell growth factors. 181 90

In cultured vascular smooth muscle cells, the baseline mRNA and protein levels of an inducible type of nitric oxide synthase were barely detectable. Interferon gamma, tumor necrosis factor-alpha, and interleukin-1 beta each markedly increased mRNA and protein levels of this enzyme in parallel with the production of nitrite, a stable oxidative metabolite of nitric oxide. Actinomycin D abolished the cytokine-induced increases in mRNA levels and nitrite production. Cycloheximide, which abolished the cytokine-induced increase in nitrite production, had no effect on the interferon-gamma-induced increase in mRNA levels but partially inhibited that induced by interleukin-1 beta and markedly inhibited that induced by tumor necrosis factor-alpha. Transforming growth factor-beta 1, which inhibited the interferon gamma-, interleukin-1 beta-, and tumor necrosis factor-alpha-induced nitrite production, did not affect the increases in mRNA levels caused by these cytokines. Transforming growth factor-beta 1, however, significantly inhibited the increase in protein levels caused by these cytokines. These findings suggest that interferon gamma directly induces the expression of the inducible nitric oxide synthase gene, whereas tumor necrosis factor-alpha and interleukin-1 beta induce it, at least in part, via the induction of intermediary protein(s), and that transforming growth factor-beta 1 inhibits cytokine-induced nitric oxide production by blocking the posttranscriptional synthesis of inducible nitric oxide synthase.
Hypertension 1994 Jan
PMID:Expression of nitric oxide synthase by cytokines in vascular smooth muscle cells. 750

The effect of cyclosporin A on induction of nitric oxide synthase in rat aortic smooth muscle cells was examined. A combination of interleukin-1 alpha (100 U/mL) and tumor necrosis factor--alpha (5000 U/mL) induced accumulation of nitrite/nitrate, the stable end products of nitric oxide, in culture media within 48 hours. Cyclosporin A inhibited this nitrite/nitrate accumulation in a concentration-dependent manner with an IC50 of 4 x 10(-7) mol/L when applied simultaneously with the cytokines. The expression of inducible nitric oxide synthase messenger RNA (mRNA) induced by the combination of interleukin-1 alpha and tumor necrosis factor-alpha was inhibited by the cyclosporin A cotreatment. Cyclosporin A did not decrease inducible nitric oxide synthase mRNA stability in the presence of transcription inhibitor actinomycin D (5 micrograms/mL). Induction of nitrite/nitrate production by the combination of tumor necrosis factor-alpha and bacterial lipopolysaccharide or that of interleukin-1 alpha and interferon gamma (100 U/mL) was also inhibited by cyclosporin A cotreatment. Another inhibitor of calcineurin, FK506 (up to 10(-6) mol/L), had no effect on the induction of nitrite/nitrate production, suggesting the possibility that the inhibitory effect of cyclosporin A may be exerted by means of a novel pathway other than inhibition of calcineurin. These results indicate that cyclosporin A inhibits inducible nitric oxide synthase induction at the mRNA level and that inducible nitric oxide synthase in vascular smooth muscle cells can be a target for cyclosporin A, providing a possible mechanism for the interference of the drug with the balance of vasoactive substances.
Hypertension 1995 Apr
PMID:Cyclosporin A inhibits nitric oxide synthase induction in vascular smooth muscle cells. 753 14

The immune system of the spontaneously hypertensive rat is dysfunctional compared with that of normotensive control strains. Previous studies from our laboratory have shown that immunodepression in the spontaneously hypertensive rat was mediated by macrophages. The current study examines the mechanism for the depressed proliferative responses to concanavalin A typically observed by splenic mononuclear cells of spontaneously hypertensive rats. We tested various inhibitors of known macrophage products responsible for suppressing lymphoid function. The nitric oxide synthetase inhibitor NG-monomethyl L-arginine produced dose-dependent derepression of the proliferative responses of splenic mononuclear cells to concanavalin A. In contrast, indomethacin and catalase exhibited only weak derepression of the proliferative responses. Subsequent analysis showed that splenic mononuclear cells from spontaneously hypertensive rats generated greater nitric oxide levels than cells from Wistar-Kyoto rats, and nitric oxide levels were reduced when the inhibitor was added to splenic mononuclear cell cultures from spontaneously hypertensive rats. We further demonstrated that L-arginine is required for the development of the depressed mitogen-induced proliferative responses in these cells. Addition of L-arginine in excess of 10 microM to cultures diminished cell proliferation and increased nitric oxide. Polyclonal antibodies to murine interferon gamma reduced nitric oxide accumulation by approximately 50%, suggesting that interferon gamma is partially responsible for enhancing nitric oxide production in mitogen-stimulated splenic mononuclear cell cultures from spontaneously hypertensive rats. Thus, this study provides evidence that the immune depression observed in the spontaneously hypertensive rat is nitric oxide dependent.
Hypertension 1993 Feb
PMID:Nitric oxide mediates immune dysfunction in the spontaneously hypertensive rat. 767 89

Cytokines and endotoxin stimulate inducible NO synthase (iNOS) in different types of cells; however, little is known about regulatory mechanisms. Using the Griess reagent for nitric levels, Western blots for iNOS protein, Northern blots for iNOS mRNA, and transient transfection studies to monitor transcription, we determined potential mechanisms involved in interleukin-1beta stimulation of iNOS in cultured neonatal ventricular myocytes. When myocytes were treated with interleukin-1beta (5 ng/mL), nitrite levels increased, and this effect was inhibited 80% by the specific iNOS inhibitor aminoguanidine. Neither interferon gamma nor tumor necrosis factor-alpha alone stimulated nitrite production. Bacterial endotoxin alone stimulated nitrites and potentiated the effect of interleukin. To determine whether a tyrosine kinase-mediated signaling pathway was involved in interleukin action, we used the inhibitor genistein, which blocked interleukin-stimulated nitrites, iNOS protein, and iNOS mRNA. To determine the effect of activation of protein kinase C, we treated cells with the phorbol ester phorbol 12-myristate 13-acetate (PMA). PMA decreased both interleukin-stimulated nitrites and iNOS protein by 40%. To determine the involvement of cyclic nucleotides, cells were treated with either dibutyryl cAMP or cGMP. cAMP (1 mmol/L) stimulated iNOS mRNA, protein, and nitrite production, whereas cGMP had no effect. To test for a direct effect of interleukin on transcription of the iNOS gene, we transfected the full-length mouse iNOS 5' regulatory sequences (-1592 to +160) coupled to a luciferase reporter gene (-1592iNOSLuc). Interleukin stimulated luciferase activity 1.8 +/- 0.2-fold. To determine whether interleukin also affects iNOS mRNA stability, interleukin-stimulated iNOS mRNA was allowed to decay in the presence of the transcription inhibitor actinomycin D. iNOS mRNA t1/2 (approximately 1 hour) was not affected by interleukin. Thus, our data suggest that (1) interleukin-1beta is the primary cytokine in myocyte iNOS regulation and acts predominantly at the transcriptional level; (2) interleukin stimulation of iNOS mRNA and protein is coupled to a tyrosine kinase-mediated signaling pathway; and (3) protein kinase C and cAMP can modify interleukin signaling by decreasing and increasing iNOS, respectively.
Hypertension 1996 Mar
PMID:Mechanisms of interleukin-1beta regulation of nitric oxide synthase in cardiac myocytes. 861 29

Although various cytokines are known to be expressed in atherosclerotic lesions, it is not known how these cytokines affect receptors for the peptide hormone angiotensin II (Ang II). We therefore examined the effects of interleukin-1 alpha (220 U/mL [10 ng/mL]), tumor necrosis factor-alpha (280 U/mL [100 ng/mL]), and interferon gamma (100 U/mL) on Ang II type 1 (AT1) receptors expressed in rat vascular smooth muscle cells. Treatment with interleukin-1 alpha caused a 1.4- to 1.7-fold increase in AT1 binding after 24 hours (P<.01) and a 2.3-fold increase in AT1 mRNA (P<.05). Tumor necrosis factor-alpha and interferon gamma did not cause a significant change in AT1 binding when administered alone but caused a 30% reduction in binding when administered together (P<.05). The maximal decrease in AT1 binding (60%, P<.01) was seen with the combination of interleukin-1 alpha with tumor necrosis factor-alpha and interferon gamma. Although the upregulation of AT1 by interleukin-1 alpha was unaffected by pretreatment of cells with N-monomethyl-L-arginine or indomethacin, downregulation of AT1 by interleukin-1 alpha combined with tumor necrosis factor-alpha/interferon gamma was inhibited by N-monomethyl-L-arginine (P<.01). Interleukin-1 alpha treatment enhanced Ang II-induced [3H]uridine incorporation, whereas treatment with interleukin-1 alpha combined with tumor necrosis factor-alpha/interferon gamma attenuated Ang II-induced [3H]uridine and [3H]leucine incorporation. These results demonstrate that interleukin-1 alpha upregulates AT1 receptors and enhances Ang II-stimulated hypertrophic responses. However, a combination of interleukin-1 alpha with tumor necrosis factor-alpha and interferon gamma downregulates AT1 receptors by a nitric oxide-dependent mechanism and reduces Ang II-stimulated trophic responses in vascular smooth muscle cells.
Hypertension 1997 Jul
PMID:Regulation of vascular type 1 angiotensin receptors by cytokines. 923 18

With a view to evaluating the putative involvement of cytokine gene variants in human essential hypertension, we carried out an association (case-control) study on 174 unrelated nationals (81 hypertensives and 93 normotensives) from the Abu Dhabi Emirate (UAE), a genetically homogeneous population also characterised by the absence of traditional confounding factors such as alcohol consumption and smoking. To that end, we targeted our investigation to five candidate gene loci-transforming growth factor beta1 (TGF-beta1), interferon gamma (IFN-gamma), epidermal growth factor (EGF), interleukin-1 beta (IL-1beta) and tumour-necrosis factor (TNF-alpha) genes. We investigated the distribution of genotypes and alleles of the six following dimorphic variants: TGF-beta1(*)10(T>C) and TGF-beta1(*)25(G>C), located at codons 10 and 25, respectively, of TGF-beta1; T874A in intron 1 of IFN-gamma; G61A in exon 1 of EGF; TaqI dimorphism at +3962 (exon 5) of IL-1beta; and -308A>G in the promoter of TNF-alpha. These six bi-allelic markers were visualised by methods based on the techniques of amplification refractory mutation system-polymerase chain reaction (for TGF-beta1, IFN-gamma, EGF and TNF-alpha) and by polymerase chain reaction-TaqI restriction endonuclease analysis in the case of IL-1beta. In each of the two groups (normotensives and hypertensives), genotype frequencies of all six markers occurred in Hardy-Weinberg proportions. There were, however, no statistical differences in the allele and genotype frequencies of any of the six markers between the two groups of subjects: TGF-beta1(*)10C frequencies were 0.46 and 0.49 (chi(2)=0.61; 2 d.f.; P=0.74) and TGF-beta1(*)25C were 0.07 and 0.08 (chi(2)=0.61; 2 d.f.; P=0.74) amongst normotensives and hypertensives, respectively; p(IFN-gamma(*)A874) were 0.41 in normotensives versus 0.46 in hypertensives (chi(2)=3.07; 2 d.f.; P=0.22); p(EGF (*)G61) were 0.51 versus 0.58 (chi(2)=1.76; 2 d.f.; P=0.41); p[IL-1beta (*)TaqI(+)] were 0.43 versus 0.36 (chi(2)=2.08; 2 d.f.; P=0.35); and p(TNF-alpha(*)-308G) were 0.80 versus 0.85 (chi(2)=1.29; 2 d.f.; P=0.53). There was also no difference in distribution and frequencies of haplotypes constructed with combinations of TGF-beta1(*)10(T>C) and TGF-beta1(*)25(G>C) sites. However, although they do not reach statistical significance (which may be due to the relatively restricted number of subjects included in this study), the distribution differences (in normotensives and hypertensives) observed in the cases of EGF and TNF-alpha reflect trends that could be expected from a mechanistic explanation of the pathways that underlie the patho-physiology of hypertension.
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PMID:A study of five human cytokine genes in human essential hypertension. 1200 75

Pathogenesis of the atherosclerotic process is deemed as multifactorial. To the most important risk factors, besides certain family predisposition, there belongs hypercholesterolemia, arterial hypertension, obesity, diabetes mellitus, smoking and others. In the last years there are more and more data about the role of inflammation and infection in the whole development of atherosclerosis. The witness for this hypothesis is the findings of high parameters of inflammation in involved vessels as well as in the blood of atherosclerosis suffering persons. Opinions about the inflammation theory appear from the 90th. Local sterile inflammation in the subendotelium of the middle and big arteries has been proved to consist of specific immune reaction (activation of the T-lymphocytes) as well as nonspecific characteristic by elevated monocytes in the artery wall during the whole process of atherogenesis. Inflammation in the plaque can trigger and hold several factors engaged in the atherosclerotic process, such as oxidized LDL cholesterol, elevated production of various superoxides, activated macrophages, activated T-lymphocytes, cytokines (IL-1, IL-6, interferon gamma) and lipoprotein Lp (a). In this inflammation process levels of CRP (acute phase protein), fibrinogen and erythrocyte sedimentation are elevated as a reaction of the organism to nonspecific chronic infections. Because of this it is thought that elevated fibrinogen and erythrocyte sedimentation are markers of the cardiovascular risk. Some papers deal with antiinflammatory effects of statins, because these lower CRP levels so they also lower atherosclerotic risk through not only lowering of cholesterol levels. Also asprine, as an antiinflammation agent, changing the CRP levels, would be of benefit for patients with vascular disease because its antiaggregation and antiinflammatory effects. ACE inhibitors are also antiinflamatory through blocking of tissue production of angiotensin II (artery wall and atherosclerotic plaque). Enzymatic inhibitors changing angiotensin can also have a partial antiinflammatory effect. The infection theory is supported also by tracing of some microorganisms in the atherosclerotic plaque or in the blood, as e.g. Helicobacter pylori or Chlamydia pneumoniae; to the autoimmune origin is indicated the presence of the specific immunity reaction against heat shock proteins (HSP) or oxidized LDL. This infection theory offers new therapy possibilities. Therefore eradication for example by antibiotics can lead to stabilization of the atherosclerotic plaque with positive consequences, as it was discovered by many studies.
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PMID:[The role of infection and inflammation in the pathogenesis of atherosclerosis]. 1219 10

Protein-losing enteropathy (PLE), the loss of plasma proteins through the intestine, is a symptom in ostensibly unrelated diseases. Emerging commonalities indicate that genetic insufficiencies predispose for PLE and environmental insults, e.g. viral infections and inflammation, trigger PLE onset. The specific loss of heparan sulfate (HS) from the basolateral surface of intestinal epithelial cells only during episodes of PLE suggests a possible mechanistic link. In the first tissue culture model of PLE using a monolayer of intestinal epithelial HT29 cells, we proved that HS loss directly causes protein leakage and amplifies the effects of the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha). Here, we extend our in vitro model to assess the individual and combined effects of HS loss, interferon gamma (IFNgamma), TNFalpha, and increased pressure, and find that HS plays a central role in the patho-mechanisms underlying PLE. Increased pressure, mimicking venous hypertension seen in post-Fontan PLE patients, substantially increased protein leakage, but HS loss, IFNgamma, or TNFalpha alone had only minor effects. However, IFNgamma up-regulated TNFR1 expression and amplified TNFalpha-induced protein leakage. IFNgamma and TNFalpha compromised the integrity of the HT29 monolayer and made it more susceptible to increased pressure. HS loss itself compromises the integrity of the monolayer, amplifying the effects of pressure, but also amplifies the effects of both cytokines. In the absence of HS a combination of increased pressure, IFNgamma, and TNFalpha caused maximum protein leakage. Soluble heparin fully compensated for HS loss, providing a reasonable explanation for patient favorable response to heparin therapy.
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PMID:Heparan sulfate plays a central role in a dynamic in vitro model of protein-losing enteropathy. 1643 7


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