Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Microvascular complications characterized by retinopathy, nephropathy, and neuropathy are highly prevalent among diabetics. Glycemic control has long been the mainstay for preventing progression of these complications; however, such control is not easily achieved. Currently, alternative adjunctive approaches to treating and preventing microvascular damage are being undertaken by targeting the molecular pathogenesis of diabetic complications. This review summarizes the specific pathogenic mechanisms of microvascular complications for which clinical therapies have been developed, including the polyol pathway, advanced glycation end products, protein kinase c, vascular epithelium growth factor, and the superoxide pathway. The review further focuses on therapies for these targets that are currently available or are undergoing late-stage clinical trials.
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PMID:Current concepts in targeted therapies for the pathophysiology of diabetic microvascular complications. 1820 Aug 3

Increased pulmonary endothelial cGMP was shown to prevent endothelial barrier dysfunction through activation of protein kinase G (PKG(I)). Vasodilator-stimulated phosphoprotein (VASP) has been hypothesized to mediate PKG(I) barrier protection because VASP is a cytoskeletal phosphorylation target of PKG(I) expressed in cell-cell junctions. Unphosphorylated VASP was proposed to increase paracellular permeability through actin polymerization and stress fiber bundling, a process inhibited by PKG(I)-mediated phosphorylation of Ser(157) and Ser(239). To test this hypothesis, we examined the role of VASP in the transient barrier dysfunction caused by H(2)O(2) in human pulmonary artery endothelial cell (HPAEC) monolayers studied without and with PKG(I) expression introduced by adenoviral infection (Ad.PKG). In the absence of PKG(I) expression, H(2)O(2) (100-250 microM) caused a transient increased permeability and pSer(157)-VASP formation that were both attenuated by protein kinase C inhibition. Potentiation of VASP Ser(157) phosphorylation by either phosphatase 2B inhibition with cyclosporin or protein kinase A activation with forskolin prolonged, rather than inhibited, the increased permeability caused by H(2)O(2). With Ad.PKG infection, inhibition of VASP expression with small interfering RNA exacerbated H(2)O(2)-induced barrier dysfunction but had no effect on cGMP-mediated barrier protection. In addition, expression of a Ser-double phosphomimetic mutant VASP failed to reproduce the protective effects of activated PKG(I). Finally, expression of a Ser-double phosphorylation-resistant VASP failed to interfere with the ability of cGMP/PKG(I) to attenuate H(2)O(2)-induced disruption of VE-cadherin homotypic binding. Our results suggest that VASP phosphorylation does not explain the protective effect of cGMP/PKG(I) on H(2)O(2)-induced endothelial barrier dysfunction in HPAEC.
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PMID:Role of vasodilator-stimulated phosphoprotein in cGMP-mediated protection of human pulmonary artery endothelial barrier function. 1828 4

1. Hesperidin, a member of the flavanone group of flavonoids, can be isolated in large amounts from the rinds of some citrus species and has been reported to have antihypotensive and vasodilator properties. However, the mechanism of action of hesperidin in the prevention and treatment of vascular diseases remains unclear. 2. The vascular endothelium can produce potent contracting factors, such as endothelin (ET)-1, and endothelium-derived relaxing factors, such as nitric oxide (NO). The aims of the present study were to test the hypothesis that hesperidin may alter strain-induced ET-1 secretion and NO production and to identify the putative underlying signalling pathways in human umbilical vein endothelial cells (HUVEC). 3. Hesperidin (10 and 100 micromol/L) inhibited strain-induced ET-1 secretion. Hesperidin also inhibited strain-induced increases in the formation of reactive oxygen species and extracellular signal-regulated kinase (ERK) phosphorylation. 4. Hesperidin treatment of HUVEC enhanced NO production, endothelial NO synthase (eNOS) activity and the phosphorylation of eNOS and Akt. Furthermore, hesperidin modulated strain-induced ET-1 release and suppressed ERK phosphorylation in part via the NO/protein kinase G pathway. 5. In summary, we have demonstrated that hesperidin inhibits strain-induced ET-1 secretion and enhances NO production in HUVEC.
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PMID:Effects of hesperidin on cyclic strain-induced endothelin-1 release in human umbilical vein endothelial cells. 1843 59

Atrial natriuretic peptide (ANP) regulates arterial blood pressure and volume. Its guanylyl cyclase-A (GC-A) receptor is expressed in vascular endothelium and mediates increases in cGMP, but the functional relevance is controversial. Notably, mice with endothelial-restricted GC-A deletion [EC GC-A knockout (KO) mice] exhibit significant chronic hypervolemic hypertension. The present study aimed to characterize the endothelial effects of ANP and their relevance for the acute regulation of intravascular fluid volume. We studied the effect of ANP on microvascular permeability to fluorescein isothiocyanate-labeled albumin (BSA) using intravital microscopy on mouse dorsal skinfold chambers. Local superfusion of ANP (100 nm) increased microvascular fluorescein isothiocyanate-BSA extravasation in control but not EC GC-A KO mice. Intravenous infusion of synthetic ANP (500 ng/kg x min) caused immediate increases in hematocrit in control mice, indicating intravascular volume contraction. In EC GC-A KO mice, the hematocrit responses were not only abolished but even reversed. Furthermore, acute vascular volume expansion, which caused release of endogenous cardiac ANP, did not affect resting central venous pressure of control mice but rapidly and significantly increased central venous pressure of EC GC-A KO mice. In cultured lung endothelial cells, ANP provoked cGMP-dependent protein kinase I-mediated phosphorylation of vasodilator-stimulated phosphoprotein. We conclude that ANP, via GC-A, enhances microvascular endothelial macromolecule permeability in vivo. This effect might be mediated by cGMP-dependent protein kinase I-dependent phosphorylation of vasodilator-stimulated phosphoprotein. Modulation of transcapillary protein and fluid transport may represent one of the most important hypovolemic actions of ANP.
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PMID:The heart communicates with the endothelium through the guanylyl cyclase-A receptor: acute handling of intravascular volume in response to volume expansion. 1845 Sep 68

Lutheran (Lu) blood group and Basal Cell Adhesion Molecule (BCAM) antigens are both carried by two glycoprotein (gp) isoforms of the immunoglobulin superfamily representing receptors for laminin alpha5 chain. They are expressed in red blood cells, in endothelial cells of vascular capillaries and in epithelial cells of several tissues. Lu/BCAM gps are overexpressed in sickle red blood cells (SS RBCs). Stimulation of SS RBCs by epinephrine activates the PKA depending signaling pathway and induces reinforced Lu/BCAM-mediated adhesion to laminin10/11. We have analyzed the phosphorylation state of Lu/BCAM long isoform cytoplasmic tail and showed that it is phosphorylated by CKII, GSK3b and PKA. Phosphorylation of this isoform in transfected K562 cells is stimulated by effectors of the PKA pathway and induces cell adhesion to laminin10/11. Lu/BCAM gps are highly expressed in endothelial cells and exhibit potential integrin binding motifs. We showed that they interact with integrin alpha4beta1, the unique integrin expressed on the surface of young reticulocytes. Adhesion assays under flow conditions showed that SS RBCs adhere to primary human endothelial cells (HUVEC) after selective activation of intergin alpha4beta1 and that this adhesion is mediated by endothelial Lu/BCAM gps. Our studies show that Lu/BCAM gps expressed either on erythroid or on endothelial cells are involved in SS RBC-endothelium interactions and could play a role in the abnormal adhesion of SS RBCs to vascular endothelium contributing to the vaso-occlusive crises reported for sickle cell disease patients.
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PMID:Role of Lu/BCAM in abnormal adhesion of sickle red blood cells to vascular endothelium. 1851 10

Tetrahydrobiopterin (BH(4)) is an essential cofactor required for enzymatic activity of endothelial NO synthase. Recently, it has been shown that vascular protective effects of erythropoietin (EPO) are dependent on activation of endothelial NO synthase. Therefore, our objective was to characterize the effect of EPO on the biosynthesis of BH(4) in the vascular wall. Incubation of isolated C57BL/6J mouse aortas for 18 hours with recombinant human EPO (1 to 50 U/mL) caused a concentration-dependent increase in intracellular BH(4) levels and activity of GTP-cyclohydrolase I. Maximal biosynthesis of BH(4) was detected at therapeutic concentrations of 5 U/mL. Removal of the endothelium abolished EPO-induced biosynthesis of BH(4) demonstrating that the vascular endothelium is a major source of BH(4). Treatment with a selective phosphatidylinositol 3-kinase inhibitor wortmannin significantly reduced BH(4) biosynthesis stimulated by EPO. The stimulatory effect of EPO on vascular GTP-cyclohydrolase I activity, BH(4) production, and phosphorylation of endothelial NO synthase was also detected in vivo in mice treated with recombinant human EPO. These effects of EPO were abolished in protein kinase Balpha/Akt1-deficient mice. In addition, EPO significantly increased systolic blood pressure and the number of circulating platelets in Akt1-deficient mice. Our results demonstrate that EPO stimulates biosynthesis of BH(4) in vascular endothelium and that the increase in BH(4) levels is caused by de novo biosynthesis of BH(4) via the phosphatidylinositol 3-kinase/Akt1 pathway. This effect is most likely designed to provide optimal intracellular concentration of the cofactor necessary for EPO-induced elevation of endothelial NO synthase activity.
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PMID:Erythropoietin increases endothelial biosynthesis of tetrahydrobiopterin by activation of protein kinase B alpha/Akt1. 1851 42

The vascular endothelium provides a semi-permeable barrier, which restricts the passage of fluid, macromolecules and cells to the surrounding tissues. Cyclic AMP promotes endothelial barrier function and protects the endothelium against pro-inflammatory mediators. This study analyzed the relative contribution of two cAMP targets, PKA and Epac1, to the control of endothelial barrier function and endothelial cell migration. Real-time recording of transendothelial electrical resistance showed that activation of either PKA or Epac1 with specific cAMP analogues increases endothelial barrier function and promotes endothelial cell migration. In addition, reduction of Epac1 expression showed that Epac1 and PKA control endothelial integrity and cell motility by two independent and complementary signaling pathways. We demonstrate that integrin-mediated adhesion is required for PKA, but not Epac1-Rap1-driven stimulation of endothelial barrier function. In contrast, both PKA- and Epac1-stimulated endothelial cell migration requires integrin function. These data show that activation of Epac1 and PKA by cAMP results in the stimulation of two parallel, independent signaling pathways that positively regulate endothelial integrity and cell migration, which is important for recovery after endothelial damage and for restoration of compromised endothelial barrier function.
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PMID:PKA and Epac1 regulate endothelial integrity and migration through parallel and independent pathways. 1863 87

Increased risk of cardiovascular disease in end-stage renal disease (ESRD) has been explained by accelerated atherosclerosis and impaired angiogenesis, in which endothelial progenitor cells (EPC) may play key roles. Circulating cells with endothelial progenitor phenotype have not been evaluated in children with ESRD. Using a quantitative reverse transcriptase polymerase chain reaction (RT-PCR) approach, we measured endothelial-specific and progenitor-associated genes VE-cadherin (VE-C), CD146, CD31, tyrosine-protein kinase receptor (Tie-2), Flk1, CD133, and growth factors promoting EPC function, vascular endothelial growth factor (VEGF), erythropoietin (EPO), and stromal cell-derived factor-1 (SDF-1) in the blood of pediatric patients undergoing hemodialysis and after transplantation. Patients' metabolic parameters were correlated with EPC marker gene levels. Compared with controls, circulating VE-cadherin, CD146, Flk1, VEGF, and EPO RNA levels were decreased in ESRD and normalized in transplanted patients. Levels of VE-cadherin, which were the most significantly reduced in ESRD (p = 0.001) inversely correlated in all of the patient population with serum urea and creatinine concentration, whereas among the ESRD group showed an inverse correlation with diastolic blood pressure (BP), interventricular septum thickness (IVST), and left ventricular mass index. Pediatric ESRD patients may have lower angiogenic potential and increased cardiovascular morbidity, because of decreased expression of circulating endothelial cell specific transcripts. Prospective studies are required to link this expression pattern and its restoration in transplanted patients to cardiovascular outcome.
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PMID:Molecular evaluation of circulating endothelial progenitor cells in children undergoing hemodialysis and after kidney transplantation. 1885 88

Argininosuccinate synthase (AS) is essential for endothelial nitric oxide (NO) production and its regulation in this capacity has been studied primarily at the transcriptional level. The dynamics of vascular function suggest that an acute regulation system may mediate AS function. This premise underlies our hypothesis that AS is phosphorylated in vascular endothelium. Immunoprecipitation and immobilized metal affinity chromatography demonstrated that AS is an endogenous phosphoprotein. An in vitro kinase screen revealed that protein kinase A (PKA), a kinase that enhances NO production via eNOS activation, phosphorylated AS. Vascular endothelial growth factor (VEGF) was identified as a candidate pathway for regulating AS phosphorylation since it enhanced NO production and activated PKA and eNOS. MDLA, an AS inhibitor, diminished maximal VEGF-mediated NO production. In addition, immunoprecipitation studies suggested that VEGF enhanced AS phosphorylation. Overall, these results represent the first demonstration that vascular endothelial NO production can be regulated by dynamic AS phosphorylation.
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PMID:Phosphorylation of argininosuccinate synthase by protein kinase A. 1894 83

It has now been over 10 years since efforts to completely understand the signalling actions of cAMP (3'-5'-cyclic adenosine monophosphate) led to the discovery of exchange protein directly activated by cAMP (EPAC) proteins. In the current review we will highlight important advances in the understanding of EPAC structure and function and demonstrate that EPAC proteins mediate multiple actions of cAMP in cells, revealing future targets for pharmaceutical intervention. It has been known for some time that drugs that elevate intracellular cAMP levels have proven therapeutic benefit for diseases ranging from depression to inflammation. The challenge now is to determine which of these positive actions of cAMP involve activation of EPAC-regulated signal transduction pathways. EPACs are specific guanine nucleotide exchange factors for the Ras GTPase homologues, Rap1 and Rap2, which they activate independently of the classical routes for cAMP signalling, cyclic nucleotide-gated ion channels and protein kinase A. Rather, EPAC activation is triggered by internal conformational changes induced by direct interaction with cAMP. Leading from this has been the development of EPAC-specific agonists, which has helped to delineate numerous cellular actions of cAMP that rely on subsequent activation of EPAC. These include regulation of exocytosis and the control of cell adhesion, growth, division and differentiation. Recent work also implicates EPAC in the regulation of anti-inflammatory signalling in the vascular endothelium, namely negative regulation of pro-inflammatory cytokine signalling and positive support of barrier function. Further elucidation of these important signalling mechanisms will no doubt support the development of the next generation of anti-inflammatory drugs.
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PMID:EPAC proteins transduce diverse cellular actions of cAMP. 1921 Jul 47


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