Hyperglycemia and reactive oxygen species mediate apoptosis in aortic endothelial cells through Janus kinase 2

Tawfik, Amany; Jin, Liming; Banes-Berceli, Amy; Caldwell, Ruth B.; Ogbi, Safia; Shirley, Amanda; Barber, Dwayne L.; Catravas, John D.; Stern, David M.; Fulton, David; Caldwell, Robert W.; Marrero, Mario B.

doi:10.1016/j.vph.2005.08.018

Cited by 37 publications

(35 citation statements)

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“…These data suggest a critical role for this pathway in vascular remodeling, which is as yet poorly understood. Previous work by our group (29) in vitro demonstrated that activation of JAK2 in the endothelial cells was detrimental to survival; however, activation of JAK2 in VSMC results in increased DNA synthesis and growth (6). These findings are further supported by our in vivo findings, which suggest that activation of JAK2 is detrimental to endothelial cell function and may result in loss of vascular function and uncontrolled VSMC growth that contributes to the development of atherosclerosis and vascular disease common to diabetes.…”

Section: Discussionsupporting

confidence: 87%

“…Inhibition of the JAK2/STAT3 pathway activation resulted in reduced neointimal formation in the injured artery, suggesting a critical role for this pathway in vascular remodeling. In addition, in aortic endothelial cells our group (29) recently showed that high glucose-induced activation of JAK2 is detrimental to cell survival in vitro. However, there is currently no data in vivo to demonstrate that activation of JAK2 is detrimental to vascular function in diabetes.…”

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confidence: 99%

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Angiotensin II and endothelin-1 augment the vascular complications of diabetes via JAK2 activation

Banes-Berceli

Ketsawatsomkron

Ogbi

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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Banes-Berceli AK, Ketsawatsomkron P, Ogbi S, Patel B, Pollock DM, Marrero MB. Angiotensin II and endothelin-1 augment the vascular complications of diabetes via JAK2 activation. Am J Physiol Heart Circ Physiol 293: H1291-H1299, 2007. First published May 25, 2007; doi:10.1152/ajpheart.00181.2007.-The JAK/STAT pathway is activated in vitro by angiotensin II (ANG II) and endothelin-1 (ET-1), which are implicated in the development of diabetic complications. We hypothesized that ANG II and ET-1 activate the JAK/ STAT pathway in vivo to participate in the development of diabetic vascular complications. Using male Sprague-Dawley rats, we performed a time course study [days 7, 14, and 28 after streptozotocin (STZ) injection] to determine changes in phosphorylation of JAK2, STAT1, and STAT3 in thoracic aorta using standard Western blot techniques. On day 7 there was no change in phosphorylation of JAK2, STAT1, and STAT3. Phosphorylation of JAK2, STAT1, and STAT3 was significantly increased on days 14 and 28 and was inhibited by treatment with candesartan (AT 1 receptor antagonist, 10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 orally in drinking water), atrasentan (ETA receptor antagonist, 10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 orally in drinking water), and AG-490 (JAK2 inhibitor, 5 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 intraperitoneally). On day 28, treatment with all inhibitors prevented the significant increase in systolic blood pressure (SBP; tail cuff) of STZ-induced diabetic rats (SBP: 157 Ϯ 9.0, 130 Ϯ 3.3, 128 Ϯ 6.8, and 131 Ϯ 10.4 mmHg in STZ, STZ-candesartan, STZ-atrasentan, and STZ-AG-490 rats, respectively). In isolated tissue bath studies, diabetic rats displayed impaired endothelium-dependent relaxation in aorta (maximal relaxation: 95.3 Ϯ 3.0, 92.6 Ϯ 7.4, 76.9 Ϯ 12.1, and 38.3 Ϯ 13.1% in sham, sham ϩ AG-490, STZ ϩ AG-490, and STZ rats, respectively). Treatment of rats with AG-490 restored endothelium-dependent relaxation in aorta from diabetic rats at 14 and 28 days of treatment. These results demonstrate that JAK2 activation in vivo participates in the development of vascular complications associated with STZinduced diabetes. vascular smooth muscle cells; type 1 diabetes; angiotensin II; Janusactivated kinase 2; signal transducer and activator of transcription COMPLICATIONS ASSOCIATED WITH type 1 and type 2 diabetes include both renal and vascular aspects. Vascular complications include an accelerated development of atherosclerosis and endothelial dysfunction (15). The loss of endothelial function has important implications for both the regulation of vascular tone and the unregulated growth of smooth muscle cells involved in the development of atherosclerosis.One activator of the tyrosine kinase Janus kinase 2 (JAK2) pathway is angiotensin II (ANG II). ANG II is involved in the vascular dysfunction and renal complications associated with many diseases, including hypertension and diabetes (27,18). In addition, our group (1, 26) has previously shown that JAK2 plays a critical role in the ANG II-and high glucose-induced growth in rat mesangial cells and ANG II-in...

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Section: Discussionsupporting

confidence: 87%

mentioning

confidence: 99%

Angiotensin II and endothelin-1 augment the vascular complications of diabetes via JAK2 activation

Banes-Berceli

Ketsawatsomkron

Ogbi

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…[2][3][4] Nevertheless, the precise mechanisms by which hyperglycemia induce pathological outcomes and the molecular nature of its downstream effectors is still a debatable issue.…”

Section: Introductionmentioning

confidence: 99%

High glucose-induced increased expression of endothelin-1 in human endothelial cells is mediated by activated CCAAT/enhancer-binding proteins

Manea¹,

Todirita²,

Heltianu³

et al. 2013

European Heart Journal

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High glucose-induced endothelial dysfunction is partially mediated by the down-stream pathophysiological effects triggered by increased expression of endothelin-1 (ET-1). The molecular control mechanisms of ET-1 synthesis are yet to be discovered. Members of the CCAAT/enhancer-binding proteins (C/EBP) family are important regulators of key metabolic processes, cellular differentiation and proinflammatory genes. In this study, we aimed at elucidating the role of C/EBP in mediating the high glucose effect on ET-1 expression in human endothelial cells (EC). Human umbilical vein cells (EAhy926) and primary cultures of human aortic EC were exposed to high levels of glucose (16.5-25 mM). Real-time PCR, Western blot, enzyme-linked immunosorbent assay, ET-1 promoter-luciferase reporter analysis, and chromatin immunoprecipitation assays were employed to investigate ET-1 regulation. High glucose activated C/EBPa, C/EBPb, and C/EBPd in a dosedependent manner. It also promoted significant increases in ET-1 gene and peptide expression. Chemical inhibition of JNK, p38MAPK and ERK1/2 diminished significantly the high glucose-induced nuclear translocation of C/EBP and ET-1 expression. Silencing of C/EBPa, C/EBPb or C/EBPd greatly reduced the high glucose-induced upregulation of ET-1 mRNA, pre-pro-ET-1, and ET-1 secretion. The expression of various C/EBP isoforms was selectively downregulated by siRNA-mediated gene silencing. In silico analysis indicated the existence of typical C/EBP elements within human ET-1 gene promoter. Transient overexpression of C/EBPa, C/EBPb or C/EBPd upregulated the luciferase level controlled by the ET-1 gene promoter. The direct interaction of C/EBPa, C/EBPb or C/EBPd proteins with the ET-1 promoter in high glucose-exposed EC was confirmed by chromatin immunoprecipitation assay. High glucose-induced ET-1 expression is mediated through multiple mechanisms. We present evidence that members of the C/EBP proinflammatory transcription factors are important regulators of ET-1 in high glucose-exposed human endothelial cells. High glucose-induced activation of C/EBP-related signaling pathways may induce excessive ET-1 synthesis, thus promoting vasoconstriction and dysfunction of the vascular wall cells in diabetes.

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“…Indeed, STAT activation was found to be induced by peroxide, but not by superoxide or nitric oxide (NO), and it was associated to an increase of the tyrosine-kinase activity of Jak2 and Tyk2 (Simon et al, 1998). Furthermore, exposure to hydrogen peroxide has been reported to induce phosphorylation of Jak2 (Tawfik et al, 2005;Yu et al, 2006). However, the specific pro-oxidant agents and the molecular mechanism underlying the latter effects remain to be clarified.…”

Section: Introductionmentioning

confidence: 99%

Exposure of glia to pro‐oxidant agents revealed selective Stat1 activation by H₂O₂ and Jak2‐independent antioxidant features of the Jak2 inhibitor AG490

Gorina

Sanfeliu

Galitó

et al. 2007

Glia

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The JAK/STAT pathway is activated in response to cytokines and growth factors. In addition, oxidative stress can activate this pathway, but the causative pro-oxidant forms are not well identified. We exposed cultures of rat glia to H2O2, FeSO4, nitroprussiate, or paraquat. We assessed oxidative stress by measuring reactive oxygen species (ROS) and oxidated proteins, we determined phosphorylated Stat1 (pStat1), and we evaluated the effect of antioxidants (trolox, propyl gallate, and N-acetylcysteine) and of Jak2 (Janus tyrosine kinases) inhibitors (AG490 and Jak2-Inhibitor-II). Pro-oxidant agents induced ROS and protein oxidation, excluding nitroprussiate that induced protein nitrosylation. H2O2, and to a lesser extent FeSO4, increased the level of pStat1, whereas nitroprussiate and paraquat did not. Trolox and propyl gallate strongly prevented ROS formation but they did not abolish H2O2-induced pStat1. In contrast, NAC did not reduce the level of ROS but it prevented the increase of pStat1 induced by H2O2, evidencing a differential effect on ROS formation and on Stat1 phosphorylation. H2O2 induced pStat1 in mixed glia cultures and, to a lesser extent, in purified astroglia, but not in microglia. Jak2 inhibitors reduced H2O2-induced pStat1, suggesting the involvement of this kinase in the increased phosphorylation of Stat1 by peroxide. Unexpectedly, AG490, but not Jak2-Inhibitor-II, reduced ROS formation, and it abrogated lipid peroxidation in microsomal preparations. Furthermore, AG490 reduced ROS in glial cells that were transfected with siRNA to silence Jak2 expression. These findings reveal previously unrecognized Jak2-independent antioxidant properties of AG490, and show that Jak2-dependent Stat1 activation by peroxide is dissociated from ROS generation.

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Hyperglycemia and reactive oxygen species mediate apoptosis in aortic endothelial cells through Janus kinase 2

Cited by 37 publications

References 21 publications

Angiotensin II and endothelin-1 augment the vascular complications of diabetes via JAK2 activation

Angiotensin II and endothelin-1 augment the vascular complications of diabetes via JAK2 activation

High glucose-induced increased expression of endothelin-1 in human endothelial cells is mediated by activated CCAAT/enhancer-binding proteins

Exposure of glia to pro‐oxidant agents revealed selective Stat1 activation by H₂O₂ and Jak2‐independent antioxidant features of the Jak2 inhibitor AG490

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Hyperglycemia and reactive oxygen species mediate apoptosis in aortic endothelial cells through Janus kinase 2

Cited by 37 publications

References 21 publications

Angiotensin II and endothelin-1 augment the vascular complications of diabetes via JAK2 activation

Angiotensin II and endothelin-1 augment the vascular complications of diabetes via JAK2 activation

High glucose-induced increased expression of endothelin-1 in human endothelial cells is mediated by activated CCAAT/enhancer-binding proteins

Exposure of glia to pro‐oxidant agents revealed selective Stat1 activation by H2O2 and Jak2‐independent antioxidant features of the Jak2 inhibitor AG490

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Exposure of glia to pro‐oxidant agents revealed selective Stat1 activation by H₂O₂ and Jak2‐independent antioxidant features of the Jak2 inhibitor AG490