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

Although conduit arteries develop hypertrophy after chronic NO synthesis blockade, resistance arteries remodel without hypertrophy under the same conditions. Similar findings have been described in essential hypertension. We postulated that this regional difference may be related to a heterogeneous effect of endogenous NO on proliferation along the vascular tree. Newly synthesized proteins were radiolabeled in vivo with [(3)H]L-leucine in basal conditions and during NO synthase inhibition, with or without PD98059 (inhibitor of the extracellular signal-regulated kinases [ERK] 1/2). Blocking the generation of NO by 3 different L-arginine analogues increased protein synthesis by an average of 75% in the aorta, in association with enhanced ERK 1/2 phosphorylation. PD98059 significantly reduced L-arginine analogue-induced protein synthesis and ERK 1/2 phosphorylation, confirming the involvement of ERK 1/2 as an important signaling element. In small arteries, L-arginine analogues did not influence the extent of protein synthesis, although phosphorylation of ERK 1/2 was also enhanced. To determine the role of NO in a condition of enhanced protein synthesis, angiotensin II was infused for 24 hours. Angiotensin II augmented protein synthesis in mesenteric arteries and the aorta, and was additive to NO synthase blockade in the aorta. In conclusion, endogenous NO exerts a tonic inhibitory influence on aortic growth, with limited impact on small arteries in basal and hypertrophic conditions. This heterogeneous role of NO on vascular growth may explain the heterogeneity of vascular remodeling observed in essential hypertension, a condition associated with endothelial dysfunction.
Hypertension 2002 Jan
PMID:Vessel-specific stimulation of protein synthesis by nitric oxide synthase inhibition: role of extracellular signal-regulated kinases 1/2. 1179 72

A host of growth factors have been implicated in vascular pathologies; one such factor is heparin-binding epidermal growth factor-like growth factor (HB-EGF). Although HB-EGF has been shown to stimulate mitogenesis and chemotaxis of vascular smooth muscle cells (VSMC), its signaling mechanism remains undefined. In this study, we examined possible signal transduction pathways by which HB-EGF leads to mitogenesis in cultured rat VSMC. HB-EGF induced phosphorylation of the EGF receptor (EGFR) with maximum phosphorylation at 0.5 to 1 minute, whereas erbB4, the other receptor to which HB-EGF binds, was not activated on HB-EGF stimulation. HB-EGF induced a time- and concentration-dependent phosphorylation of mitogen-activated protein kinase (MAPK; p42/44 MAPK, extracellular signal-regulating kinase [ERK] 1/2). It also activated Akt and p70S6 kinase (p70S6K) but not p38 MAPK. HB-EGF-induced phosphorylation of these kinases was blocked by the EGFR kinase inhibitor AG1478. To investigate signaling molecules involved in HB-EGF-induced DNA synthesis, we pretreated VSMC with the specific ERK kinase mitogen-activated kinase (MEK) inhibitor PD98059 and the phosphatidylinositol 3-kinase inhibitor LY294002. These inhibitors significantly blocked HB-EGF-induced DNA synthesis. PD98059 inhibited HB-EGF-induced ERK activation, whereas it had no effect on Akt activation by HB-EGF. By contrast, LY294002 inhibited HB-EGF-induced Akt and p70S6K activation without effecting ERK activation by HB-EGF. These results demonstrate that HB-EGF-induced mitogenesis requires both ERK and phosphatidylinositol 3-kinase (Akt and p70S6K) pathways activated through EGFR, thereby providing a new mechanistic insight by which HB-EGF contributes to vascular remodeling.
Hypertension 2002 Feb
PMID:Signaling mechanisms of heparin-binding epidermal growth factor-like growth factor in vascular smooth muscle cells. 1188 2

Some beneficial effects of angiotensin-I--converting enzyme (ACE, kininase II) inhibitor therapy are attributed to enhancing the activity of bradykinin on its B(2) receptor. Independent of inhibition of bradykinin hydrolysis, ACE inhibitors enhance the action of bradykinin on its B(2) receptor by inducing crosstalk between ACE and the receptor. We investigated whether inhibitors of another kininase II-type enzyme, neprilysin (neutral endopeptidase 24.11; NEP), could augment bradykinin effects unrelated to blocking its breakdown using a NEP-resistant bradykinin analog as ligand. We used transfected Chinese hamster ovary (CHO) cells stably expressing human B(2) receptor and NEP (CHO/NEP-B(2)) or only B(2) (CHO/B(2)) as control and human pulmonary fibroblasts (IMR90), expressing B(2), but more NEP than ACE. NEP inhibitor phosphoramidon (100 nmol/L), or omapatrilat, which inhibits both NEP and ACE, did not potentiate bradykinin in CHO/B(2) cells. In IMR90 cells, 10 nmol/L bradykinin elevated [Ca(2+)](i) and desensitized the receptor. Adding either 100 nmol/L omapatrilat or phosphoramidon resensitized the receptor to the ligand, which was abolished by receptor blocker HOE 140. Arachidonic acid release by bradykinin from CHO/NEP-B(2) cells was also augmented by 100 nmol/L phosphoramidon or omapatrilat about 3-fold, and again, the inhibitors resensitized the desensitized B(2) receptor. The inhibitors did not potentiate bradykinin when soluble rNEP was added to the medium of CHO/B(2) cells. Similar to ACE, NEP inhibitors potentiated bradykinin independent of inhibiting inactivation. Consequently, omapatrilat could augment bradykinin effects on B(2), when either ACE or NEP is expressed close to receptor on cell membrane.
Hypertension 2002 Feb
PMID:Neprilysin inhibitors potentiate effects of bradykinin on b2 receptor. 1188 19

This study investigated mechanisms underlying native low-density lipoprotein (LDL)-stimulated proliferation of human vascular smooth muscle cells (VSMC). Experiments were performed to determine whether native LDL affects reactive oxygen species (ROS) formation and activity of extracellular signal-regulated kinase 1/2 (ERK1/2), and whether redox-sensitive pathways contribute to LDL-induced cell proliferation. Native LDL (100 microg/mL, 24 hours) increased cell proliferation (to 303 to 388% of control, P<0.0001) as determined by [methyl-(3)H] thymidine incorporation. This effect was completely blocked either by the antioxidants N-acetylcysteine, Tiron, or nordihydroguaiaretic acid; the flavin-inhibitor diphenylene iodonium; or superoxide dismutase (all P<0.0001), and partly blocked by ERK-inhibitor PD98059 or meclofenamate (P<0.01). Exposure of VSMC to native LDL for 20 minutes stimulated ROS formation, measured by dichlorodihydrofluorescein oxidation, and increased ERK1/2 activity by 3.1-fold (P<0.001). The latter effect was sensitive to MEK1/2 inhibitor PD98059 and Tiron (P<0.001), and in part to N-acetylcysteine or diphenylene iodonium (P<0.05). These results demonstrate that native LDL induces acute formation of ROS and subsequent activation of redox-sensitive ERK 1/2 mitogen-activated protein kinases, pathways that appear to be important for mitogenic signaling of native LDL in human vascular smooth muscle cells.
Hypertension 2002 Feb
PMID:Native LDL induces proliferation of human vascular smooth muscle cells via redox-mediated activation of ERK 1/2 mitogen-activated protein kinases. 1188 24

To explore the role of platelet derived growth factor-AA (PDGF-AA) and PDGFR-alpha expression in the proliferation and hypertrophy of vascular smooth muscle cells (VSMCs) in spontaneously hypertension rats (SHR), protein expression of PDGF-AA, PDGFR-alpha and PDGFR-beta in SHR/Wistar-Kyoto (WKY)-VSMC was observed by Western blot. Proliferation and hypertrophy of SHR-VSMCs induced by PDGF-AA were observed by measurement of PCNA and [(3)H] incorporation. PDGF-AA and PDGFR-alpha expression was markedly increased in SHR-VSMCs compared with that in WKY-VSMCs, but PDGFR-beta was not different in SHR and WKY-VSMCs. PDGF-AA induced PCNA expression and [(3)H] incorporation was increased in a dose-dependent manner in SHR, but not in WKY. It is suggested that an enhancement of PDGF-AA and PDGFR-alpha in SHRs may be one of the important factors for vascular modeling.
 ...
PMID:[Relationship between proliferation of vascular smooth muscle cells and PDGF-AA and PDGFR-alpha expression in SHRs]. 1197 95

Vascular endothelial growth factor (VEGF) exerts vasodilation-induced hypotension as a major side effect for treatment of ischemic diseases. VEGF has 2 receptor tyrosine kinases, KDR and Flt-1. Little is known about which receptor mediates VEGF-induced hypotension. To elucidate the role of each receptor in mediating hypotension, KDR-selective and Flt-1-selective mutants were used for in vitro and in vivo studies. The KDR-selective mutant induced vascular endothelial cell proliferation comparable to VEGF, whereas the Flt-1- selective mutant had no effect on proliferation. Intravenous injection of KDR-selective mutant, Flt-selective mutant, or VEGF caused a dose-related decrease in mean arterial pressure in conscious rats. The hypotensive response to KDR-selective mutant was significantly less than that to VEGF (P<0.01) but was greater than that to Flt-selective mutant (P<0.01). Similarly, VEGF and KDR-selective mutant induced more potent vasorelaxation than Flt-selective mutant or placenta growth factor that binds Flt-1 only (P<0.01), and the vasorelaxation to KDR-selective mutant was not significantly different at low concentrations but less than that to VEGF at high concentrations. The results indicate that the vasodilation and hypotensive effect of VEGF may involve both receptors, but KDR is the predominant receptor mediating this effect. Because KDR-selective mutant induced proliferation and angiogenesis similar to VEGF but was associated with 36% attenuation in hypotension, the data suggest that the KDR-selective mutant may represent an alternative treatment for ischemic diseases.
Hypertension 2002 Jun
PMID:KDR (VEGF receptor 2) is the major mediator for the hypotensive effect of VEGF. 1205 48

Bilateral coronal synostosis causes functional and morphological problems that require fronto-orbital advancement in infancy to correct the brachycephalic deformity and to prevent mental impairment caused by the intracranial hypertension. In this study, 99 children with isolated cases of brachycephaly were prospectively followed to study their preoperative and postoperative mental outcome, which was evaluated using developmental or intelligence quotients. Several factors were analyzed: age before treatment, age at the time of surgery, and the correlation between mental assessments before and after surgery. In a subgroup or patients tested for the FGFR3 P250R mutation (n = 48), mental and morphological assessments were analyzed. Before surgery, mental status was better in the patients tested before 1 year of age (p < 0.001). The preoperative mental assessment always correlated with the postoperative assessment (p < 0.0001). The postoperative mental outcome was better when surgery was performed before the patient reached 1 year of age (p < 0.02). Although both the morphological and functional outcomes were better in the subgroup of noncarriers of the mutation, the differences were not statistically significant. Prominent bulging of the temporal fossae was frequently responsible for poor morphological outcome in carriers of the mutation. This study confirms the need for early corrective surgery before 1 year of age in brachycephalic patients to prevent impairment of their mental development. Suboptimal morphological and mental outcomes can be expected in patients with nonsyndromic brachycephaly who carry the FGFR3 P250R mutation. Primary correction of the temporal bulging should be performed in conjunction with fronto-orbital advancement to improve the morphological outcome in patients with the mutation.
 ...
PMID:Postoperative mental and morphological outcome for nonsyndromic brachycephaly. 1208 22

Activation of the local and systemic renin-angiotensin system is directly and indirectly involved in mechanisms of vascular remodeling during chronic hypertension. This study investigated the effect of angiotensin II (AII) on rat vascular smooth muscle cell (VSMC) migration towards platelet-derived growth factor-BB (PDGF-BB) in vitro. Pre-treatment with AII (1 microM) for 48 or 72 h induced a significant increase in PDGF-BB-directed migration by 77 +/- 21 % and 58 +/- 24 %, respectively (both p < 0.01). This effect was concentration dependent and inhibited by the selective angiotensin receptor type I (AT(1)) blocker DUP 753. PDGF-directed migration of VSMCs was significantly inhibited by antibodies against beta(3)-and beta(5)-integrins, indicating an important role of these integrins in VSMC migration. However, AII augmented migration was not accompanied by an increased expression of beta(3)- and beta(5)-integrin mRNA and protein levels in VSMCs. Inhibition of the mitogen-activated protein kinase ERK 1/2 with PD 98059 (30 microM) completely abolished the effect of AII on PDGF-BB-directed VSMC migration (p < 0.01). The proline-rich tyrosine kinase 2 (Pyk2) and focal adhesion kinase (FAK) are cytoskeleton-associated protein kinases participating in integrin-dependent signaling. Therefore, expression and phosphorylation of these kinases was determined 48 h after AII treatment, revealing a significant increase in Pyk2 and FAK protein levels (up to 2-fold, both p < 0.05) and increased phosphorylation of Pyk2 (2-fold, p < 0.05) and ERK 1/2 (4-fold, p < 0.05) as compared to controls. Furthermore, immunofluorescence and Western blot analysis demonstrated a translocation of Pyk2 from the plasma membrane to the cytosol, as well as a perinuclear enrichment of ERK 1/2 protein 48 h after AII treatment. In conclusion, our data suggest that changes in the levels of Pyk2 and ERK 1/2 phosphorylation, responsible for integrin-dependent signaling, as well as their subcellular translocation are important for the enhanced chemotactic response of VSMCs after AII pre-treatment.
 ...
PMID:Angiotensin II-augmented migration of VSMCs towards PDGF-BB involves Pyk2 and ERK 1/2 activation. 1211 Oct 44

Reports on the association of papillary thyroid carcinoma with paraganglionic or desmoid tumors have appeared infrequently. The former setting usually affects middle-aged females; the latter is typical of familial adenomatous polyposis. We report the case of a 69-yr-old man in whom two abdominal masses had been instrumentally detected following an access of abdominal pain. Save for a moderate hypertension, he was asymptomatic and an impalpable thyroid nodule was detected by ultrasonography. A high urinary noradrenaline output and cytology of the masses raised the suspicion of pheochromocytoma. At laparotomy, an adrenal pheochromocytoma and a paracaval paraganglioma were excised. Subsequently, hemithyroidectomy was performed, and histopathology revealed papillary microcarcinoma. A nodule of desmoid tumor was also removed from the abdominal wall. An analysis of RET, APC, and TP53 gene mutations, and of RET and NTRK1 gene rearrangements, yielded negative results. No in vitro transforming activity was detected in the tumor DNA when assayed in transfection experiments. The lack of a consistent family history also made unlikely the possibility of identifying the putative germline defect by linkage analyses. Should this unusual aggregation of tumors represent a new entity, a number of genetic alterations have now been excluded.
 ...
PMID:Concurrent Pheochromocytoma, Paraganglioma, Papillary Thyroid Carcinoma, and Desmoid Tumor: A Case Report with Analyses at the Molecular Level. 1211 65

Angiotensin II (Ang II) is a multifunctional hormone that influences the function of cardiovascular cells through a complex series of intracellular signaling events initiated by the interaction of Ang II with AT1 and AT2 receptors. AT1 receptor activation leads to cell growth, vascular contraction, inflammatory responses and salt and water retention, whereas AT2 receptors induce apoptosis, vasodilation and natriuresis. These effects are mediated via complex, interacting signaling pathways involving stimulation of PLC and Ca2+ mobilization; activation of PLD, PLA2, PKC, MAP kinases and NAD(P)H oxidase, and stimulation of gene transcription. In addition, Ang II activates many intracellular tyrosine kinases that play a role in growth signaling and inflammation, such as Src, Pyk2, p130Cas, FAK and JAK/STAT. These events may be direct or indirect via transactivation of tyrosine kinase receptors, including PDGFR, EGFR and IGFR. Ang II induces a multitude of actions in various tissues, and the signaling events following occupancy and activation of Ang receptors are tightly controlled and extremely complex. Alterations of these highly regulated signaling pathways may be pivotal in structural and functional abnormalities that underlie pathological processes in cardiovascular diseases such as cardiac hypertrophy, hypertension and atherosclerosis.
 ...
PMID:Recent advances in angiotensin II signaling. 1221 72


<< Previous 1 2 3 4 5 6 7 8 9 10