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:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Maternal endothelial dysfunction in preeclampsia is associated with increased soluble fms-like tyrosine kinase-1 (sFlt-1), a circulating antagonist of vascular endothelial growth factor and placental growth factor. Angiotensin II (Ang II) is a potent vasoconstrictor that increases concomitant with sFlt-1 during pregnancy. Therefore, we speculated that Ang II may promote the expression of sFlt-1 in pregnancy. Here we report that infusion of Ang II significantly increases circulating levels of sFlt-1 in pregnant mice, thereby demonstrating that Ang II is a regulator of sFlt-1 secretion in vivo. Furthermore, Ang II stimulated sFlt-1 production in a dose- and time-dependent manner from human villous explants and cultured trophoblasts but not from endothelial cells, suggesting that trophoblasts are the primary source of sFlt-1 during pregnancy. As expected, Ang II-induced sFlt-1 secretion resulted in the inhibition of endothelial cell migration and in vitro tube formation. In vitro and in vivo studies with losartan, small interfering RNA specific for calcineurin and FK506 demonstrated that Ang II-mediated sFlt-1 release was via Ang II type 1 receptor activation and calcineurin signaling, respectively. These findings reveal a previously unrecognized regulatory role for Ang II on sFlt-1 expression in murine and human pregnancy and suggest that elevated sFlt-1 levels in preeclampsia may be caused by a dysregulation of the local renin/angiotensin system.
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PMID:Angiotensin II induces soluble fms-Like tyrosine kinase-1 release via calcineurin signaling pathway in pregnancy. 1715 38

Discovered in fungi in the remote Easter Island, sirolimus (rapamycin) shows potential beyond its obvious antiproliferative and immunosuppressant activity. Studies have demonstrated that sirolimus acts as a vascular endothelial growth factor inhibitor, providing prospective therapeutic benefits and possible prevention of tuberous sclerosis and Kaposi's sarcoma. Its ability to decrease keratinocyte proliferation may help patients with psoriasis. In those with tuberous sclerosis complex, it may prevent the development of hamartomas and reduce or eliminate them once grown by blocking the mammalian target of rapamycin, a critical regulatory kinase. A great advantage for this drug is in the decreased risk of malignancies, including Kaposi's sarcoma, associated with its use compared with other immunosuppressants, namely calcineurin inhibitors. This review will focus on the pharmacology and potential uses of sirolimus.
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PMID:Sirolimus (rapamycin): from the soil of Easter Island to a bright future. 1758 72

In endothelial cells, binding of vascular endothelial growth factor (VEGF) to VEGF receptor 2 leads to the activation of the serine/threonine phosphatase calcineurin, dephosphorylation of the nuclear factor of activated T-cells (NF-AT) transcription factors, translocation of NF-AT to the nucleus, and expression of angiogenesis-related genes such as Cox-2. Down syndrome candidate region 1 (DSCR1) is transactivated by NF-AT nuclear translocation, and subsequently inhibits calcineurin activity, forming a negative feedback loop. While DSCR1 has a clearly defined role as an endogenous inhibitor of VEGF-calcineurin-mediated angiogenesis in endothelial cells, the function of the DSCR1 family member, DSCR1-like 1 (DSCR1-L1), has not yet been investigated in endothelial cells. Here we show that a panel of pro-angiogenic factors, including VEGF, basic fibroblast growth factor (bFGF), angiopoietin 1, hepatocyte growth factor, as well as triiodo-l-thyronine (T(3)), does not induce DSCR1-L1 up-regulation in endothelial cells, while VEGF potently up-regulates DSCR1. To investigate the effects of DSCR1-L1 on endothelial cell function, we cloned the gene into a lentiviral vector and overexpressed DSCR1-L1 in human umbilical vein endothelial cells. Constitutive DSCR1-L1 overexpression prevented the nuclear translocation of NF-ATc1 in response to VEGF, underscoring its role as a calcineurin inhibitor. Additionally, DSCR1-L1-transduced cells inhibited VEGF-induced endothelial cell migration, proliferation, and tube formation by 36, 77, and 39%, respectively, compared to cells infected with control virus. Overexpression of DSCR1-L1 in the transformed endothelial cell line Sven 1 ras also resulted in decreased proliferation. Our findings demonstrate that DSCR1-L1 is constitutively expressed in endothelial cells and acts similar to DSCR1 in inhibiting calcineurin activity and restraining VEGF-mediated angiogenesis.
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PMID:Down syndrome candidate region 1-like 1 (DSCR1-L1) mimics the inhibitory effects of DSCR1 on calcineurin signaling in endothelial cells and inhibits angiogenesis. 1761 Sep 1

The evaluation of signaling pathways leading to gene induction by VEGF-A and IL-1 in endothelial cells supports the importance of the NF-kappaB pathway for the IL-1-induced gene repertoire, whereas VEGF-A is a strong and preferential trigger of signals via PLC-gamma. This leads (i) via Ca(++) to the activation of calcineurin and NFAT and (ii) via PKC and the MEK/ERK MAPK pathway to the upregulation of EGR-1. Part of the VEGF-triggered gene induction depends on a cooperation of the transcription factors NFAT and EGR-1. Gene activation via PLC-gamma provides VEGF with the potency to induce a wide spectrum of genes including many also upregulated by IL-1. A gene upregulated by VEGF and IL-1 is the DSCR-1 gene, which encodes an inhibitor of calcineurin. DSCR1 is induced by NFAT or NF-kappaB and limits Ca(++) signaling in a negative feed-back loop. Similarly, NAB2, a corepressor of EGR-1, is induced by EGR-1 and limits EGR-1 effects. Adenoviral overexpression of DSCR1 or NAB2 inhibited part of VEGF-induced gene expression and reduced sprouting in angiogenesis models.
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PMID:Signals and genes induced by angiogenic growth factors in comparison to inflammatory cytokines in endothelial cells. 1764 95

Sirolimus has been associated with high-range proteinuria when used in replacement of calcineurin inhibitors in renal transplant recipients with chronic allograft nephropathy (CAN). Primary FSGS was demonstrated previously in some such patients, but the coexistence of CAN lesions made the interpretation uneasy. However, nephrotic syndrome and FSGS were observed recently in three patients who received sirolimus de novo, without medical history of primary FSGS or CAN. Markers of podocyte differentiation were studied in kidney biopsies of the three patients who received sirolimus de novo and of five patients who switched to sirolimus. All patients developed FSGS lesions of classic type (not otherwise specified), but only switched patients exhibited advanced sclerotic lesions. Immunohistochemistry showed that some podocytes in FSGS lesions had absent or diminished expression of the podocyte-specific epitopes synaptopodin and p57, reflecting dedifferentiation, and had acquired expression of cytokeratin and PAX2, reflecting a immature fetal phenotype. Such a pattern of epitope expression provides evidence for podocyte dysregulation. Moreover, a decrease in vascular endothelial growth factor expression was observed in some glomeruli. In conclusion, sirolimus induces FSGS that is responsible for proteinuria in some transplant patients.
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PMID:High sirolimus levels may induce focal segmental glomerulosclerosis de novo. 1769 6

Cigarette smoke contains hundreds of potentially toxic compounds and is an important risk factor for cardiovascular disease. However, the key components responsible for endothelial and myocardial dysfunction have not been fully identified. The objective of the present study was to determine the cardiovascular effects of long-term inhalation of carbon monoxide (CO) administrated to give concentrations in the blood similar to those observed in heavy smokers. Female rats were exposed to either CO or air (control group) (n = 12). The CO group was exposed to 200 ppm CO (100 h/wk) for 18 mo. Rats exposed to CO had 24% lower maximal oxygen uptake, longer (145 vs. 123 microm) and wider (47 vs. 25 microm) cardiomyocytes, reduced cardiomyocyte fractional shortening (12 vs. 7%), and 26% longer time to 50% re-lengthening than controls. In addition, cardiomyocytes from CO-exposed rats had 48% lower intracellular calcium (Ca2 +) amplitude, 22% longer time to Ca2 + decay, 34% lower capacity of sarcoplasmic reticulum Ca2 +-ATPase (SERCA2a), and 37% less t-tubule area compared to controls. Phosphorylation levels of phospholamban at Ser16 and Thr17 were significantly reduced in the CO group, whereas total concentration of phospholamban and SERCA2a were unchanged. Cardiac atrial natriuretic peptide, vascular endothelial growth factor, cyclic guanosine monophosphate, calcineurin, calmodulin, pERK, and pS6 increased, whereas pAkt and pCaMKII delta remained unchanged by CO. Endothelial function and systemic blood pressure were not affected by CO exposure. Long-term CO exposure reduces aerobe capacity and contractile function and leads to pathological hypertrophy. Impaired Ca2 + handling and increased growth factor signaling seem to be responsible for these pathological changes.
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PMID:Carbon monoxide levels experienced by heavy smokers impair aerobic capacity and cardiac contractility and induce pathological hypertrophy. 1846 52

Cancer is an increasing and major problem after solid organ transplantation. In part, the increased cancer risk is associated with the use of immunosuppressive agents, especially calcineurin inhibitors. We propose that the effect of calcineurin inhibitors on the expression of vascular endothelial growth factor (VEGF) leads to an angiogenic milieu that favors tumor growth. Here, we used 786-0 human renal cancer cells to investigate the effect of cyclosporine (CsA) on VEGF expression. Using a full-length VEGF promoter-luciferase construct, we found that CsA markedly induced VEGF transcriptional activation through the protein kinase C (PKC) signaling pathway, specifically involving PKC zeta and PKC delta isoforms. Moreover, CsA promoted the association of PKC zeta and PKC delta with the transcription factor Sp1 as observed by immunoprecipitation assays. Using promoter deletion constructs, we found that CsA-mediated VEGF transcription was primarily Sp1 dependent. Furthermore, CsA-induced and PKC-Sp1-mediated VEGF transcriptional activation was partially inhibited by von Hippel-Lindau protein. CsA also promoted the progression of human renal tumors in vivo, wherein VEGF is overexpressed. Finally, to evaluate the in vivo significance of CsA-induced VEGF overexpression in terms of post-transplantation tumor development, we injected CT26 murine carcinoma cells (known to form angiogenic tumors) into mice with fully MHC mismatched cardiac transplants. We observed that therapeutic doses of CsA increased tumor size and VEGF mRNA expression and also enhanced tumor angiogenesis. However, coadministration of a blocking anti-VEGF antibody inhibited this CsA-mediated tumor growth. Collectively, these findings define PKC-mediated VEGF transcriptional activation as a key component in the progression of CsA-induced post-transplantation cancer.
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PMID:Overexpression of vascular endothelial growth factor and the development of post-transplantation cancer. 1863 21

Okadaic acid, a potent tumor promoter and an inhibitor of protein phosphatase 1 and 2A, has also been characterized as an angiogenic inducer in the chorioallantoic membrane of the chick embryo. To elucidate the roles of okadaic acid on angiogenic processes, we conducted in vitro angiogenesis assays. In this study, we report that okadaic acid potently stimulated tube formation, migration, and invasion of human umbilical vein endothelial cells. Moreover, okadaic acid elevated the activities of hypoxia-inducible factor-1 (HIF-1), which is closely related with the expression of vascular endothelial growth factor. Exposure to okadaic acid markedly increased the HIF-1alpha protein level through up-regulation of translation via activation of Akt and mTOR pathway. Taken together, these results demonstrated that okadaic acid promotes angiogenesis through stimulation of Akt mediated HIF-1alpha translation.
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PMID:Okadaic acid promotes angiogenesis via activation of hypoxia-inducible factor-1. 1905 10

NFATc1 transcription factor is critical for lineage selection in T-cell differentiation, cardiac valve morphogenesis and osteoclastogenesis. We identified a role for calcineurin-NFAT signaling in lymphatic development and patterning. NFATc1 was colocalized with lymphatic markers Prox-1, VEGFR-3 and podoplanin on cardinal vein as lymphatic endothelial cells (LEC) are specified and as they segregate into lymph sacs and mature lymphatics. In NFATc1 null mice, Prox-1, VEGFR-3 and podoplanin positive endothelial cells sprouted from the cardinal vein at E11.5, but poorly coalesced into lymph sacs. NFAT activation requires the phosphatase calcineurin. Embryos treated in utero with the calcineurin inhibitor cyclosporine-A showed cytoplasmic NFATc1, diminished podoplanin and FGFR-3 expression by the lymphatics and irregular patterning of the LEC sprouts coming off the jugular lymph sac, which suggests a role for calcineurin-NFAT signaling in lymphatic patterning. In a murine model of injury-induced lymphangiogenesis, NFATc1 was expressed on the neolymphatics induced by lung-specific overexpression of VEGF-A. Mice lacking the calcineurin Abeta regulatory subunit, with diminished nuclear NFAT, failed to respond to VEGF-A with increased lymphangiogenesis. In vitro, endogenous and VEGF-A-induced VEGFR-3 and podoplanin expression by human microvascular endothelial cells was reduced by siRNA to NFATc1, to levels comparable to reductions seen with siRNA to Prox-1. In reporter assays, NFATc1 activated lymphatic specific gene promoters. These results demonstrate the role of calcineurin-NFAT pathway in lymphangiogenesis and suggest that NFATc1 is the principle NFAT involved.
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PMID:NFATc1 regulates lymphatic endothelial development. 1923 65

Skin cancers are the most common tumors among transplant recipients who receive immunosuppressive agents. Kaposi sarcoma (KS) is one of the most common malignancies to occur in kidney transplant recipients, especially in the Middle East countries. Its prevalence in comparison with other neoplasms is also relatively higher in Iran (> 35%). The KS-associated herpesvirus or human herpesvirus 8 is a newly discovered herpesvirus found in all forms of the KS including those among immunosuppressed transplant recipients. Kaposi sarcoma usually regresses after withdrawal or reduction of immunosuppressive agents. A wide variety of therapies have been used for KS, including radiotherapy and administration of interferon and different chemotherapeutic regimens. Sirolimus exhibits antiangiogenic activity related to impaired production of vascular endothelial growth factor and limited proliferative response of endothelial cells to the stimulation by vascular endothelial growth factor. Therefore, it can inhibit the progression of KS. Accordingly, replacement of calcineurin inhibitors by a sirolimus can show promising results in the prevention of KS.
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PMID:Kaposi sarcoma after kidney transplantation. 1935 36


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