scholarly journals Selective Astrocytic Endothelin-1 Overexpression Contributes to Dementia Associated with Ischemic Stroke by Exaggerating Astrocyte-Derived Amyloid Secretion

2015 ◽  
Vol 35 (10) ◽  
pp. 1687-1696 ◽  
Author(s):  
Victor KL Hung ◽  
Patrick KK Yeung ◽  
Angela KW Lai ◽  
Maggie CY Ho ◽  
Amy CY Lo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cognitive Deficits ◽  
In Vitro Study ◽  
Artery Occlusion ◽  
Spatial Learning And Memory ◽  
Dependent Manner ◽  
Endothelin 1 ◽  
Endothelin B

Endothelin-1 (ET-1) is synthesized by endothelial cells and astrocytes in stroke and in brains of Alzheimer's disease patients. Our transgenic mice with ET-1 overexpression in the endothelial cells (TET-1) showed more severe blood–brain barrier (BBB) breakdown, neuronal apoptosis, and glial reactivity after 2-hour transient middle cerebral artery occlusion (tMCAO) with 22-hour reperfusion and more severe cognitive deficits after 30 minutes tMCAO with 5 months reperfusion. However, the role of astrocytic ET-1 in contributing to poststroke cognitive deficits after tMCAO is largely unknown. Therefore, GET-1 mice were challenged with tMCAO to determine its effect on neurologic and cognitive deficit. The GET-1 mice transiently displayed a sensorimotor deficit after reperfusion that recovered shortly, then more severe deficit in spatial learning and memory was observed at 3 months after ischemia compared with that of the controls. Upregulation of TNF- a, cleaved caspase-3, and Thioflavin-S-positive aggregates was observed in the ipsilateral hemispheres of the GET-1 brains as early as 3 days after ischemia. In an in vitro study, ET-1 overexpressing astrocytic cells showed amyloid secretion after hypoxia/ischemia insult, which activated endothelin A (ETA) and endothelin B (ETB) receptors in a PI3K/AKT-dependent manner, suggesting role of astrocytic ET-1 in dementia associated with stroke by astrocyte-derived amyloid production.

Abstract 570: Cystathionine γ-Lyase Modulates Flow-dependent Vascular Remodeling

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Shuai Yuan ◽  
Arif Yurdagul ◽  
Jonette M Green ◽  
Sibile Pardue ◽  
Christopher G Kevil ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Remodeling ◽  
Oscillatory Flow ◽  
Carotid Arteries ◽  
Dependent Manner ◽  
Disturbed Flow ◽  
Sulfane Sulfur ◽  
Nitrite Level

Disturbed flow causes endothelial dysfunction and development of atherosclerotic lesions. The gaseous signaling molecule H 2 S and cystathionine γ-lyase (CSE), its major enzymatic source in the vasculature, protect against cardiovascular diseases including atherosclerosis, peripheral artery disease, and cardiac ischemia in a nitric oxide (NO) dependent manner. Therefore, we sought to investigate the role of CSE in the endothelial response to disturbed flow. Wild-type C57Bl/6 (WT) and CSE knockout (CSE-/-) mice underwent partial carotid ligation to induce disturbed flow in the left carotid with the right carotid serving as an internal control. Additionally, endothelial cells isolated from WT and CSE-/- mice were exposed to oscillatory flow, a model of disturbed flow, in vitro. While disturbed flow decreased endothelial CSE mRNA expression, CSE protein expression showed strong induction under disturbed flow conditions both in vitro and in vivo. This induction correlated with enhanced free sulfide and sulfane sulfur production in WT but not in CSE-/- mice. Intimal mRNA isolated 2 days post-ligation showed increased VCAM-1 and ICAM-1 expression in WT mice which was prevented in CSE-/- mice. Similarly, endothelial cells isolated from CSE-/- mice show reduced NF-B activation and proinflammatory gene expression in response to oscillatory flow in vitro. Morphometric analysis of carotid arteries collected 7 days post-ligation revealed reduced macrophage infiltration and medial thickening in the ligated carotid of CSE-/- mice. Interestingly, ligation increased the carotid nitrite level in WT mice but not in CSE-/- mice. However, nitrite level of the non-ligated carotid was significantly higher in the CSE-/- mice compared to WT mice. Shear induced phosphorylation of eNOS Ser1179 in vitro was not different between WT and CSE knockout endothelial cells, suggesting alternative regulatory mechanisms. Collectively, CSE in mouse carotid arteries plays a critical role in flow dependent vascular remodeling, which may be mediated by CSE derived free sulfide and sulfane sulfur. CSE deficiency completely inhibits disturbed flow-induced NF-κB activation and macrophage recruitment, consistent with the role of inflammation in vascular remodeling.

Angiotensin II increases the release of endothelin-I from human cultured endothelial cells but does not regulate its circulating levels

1999 ◽  
Vol 96 (3) ◽  
pp. 261-270 ◽  
Author(s):  
Claudio FERRI ◽  
Giovambattista DESIDERI ◽  
Roberta BALDONCINI ◽  
Cesare BELLINI ◽  
Marco VALENTI ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Protein Synthesis ◽  
Angiotensin Ii ◽  
At1 Receptor ◽  
Dependent Manner ◽  
Synthesis Inhibitor ◽  
Endothelin 1 ◽  
Cultured Endothelial Cells

We investigated the effect of angiotensin II on endothelin-1 secretion in vitro and in vivo. In vivo, angiotensin II was given intravenously to 23 essential hypertensive and 8 control subjects according to different protocols: Study A, 1.0 ngċmin-1ċkg-1 and 3.0 ngċmin-1ċkg-1 angiotensin II for 30 min each; Study B, 1.0 ngċmin-1ċkg-1 and 3.0 ngċmin-1ċkg-1 angiotensin II for 120 min each; Study C, 3.0 ngċmin-1ċkg-1 angiotensin II for 30 min followed by a dose increment of 3.0 ngċmin-1ċkg-1 every 30 min until mean blood pressure levels increased by 25 mmHg; Study D, 1.0 ngċmin-1ċkg-1 followed by 3.0 ngċmin-1ċkg-1 angiotensin II for 60 min each on two different NaCl diets (either 20 mmol NaCl/day or 220 mmol NaCl/day, both for 1 week). In all in vivo studies neither plasma nor urine endothelin-1 levels changed with angiotensin II infusion. In contrast, angiotensin II (10-9, 10-8, 10-7 mol/l) stimulated endothelin-1 secretion from cultured human vascular endothelial cells derived from umbilical cord veins in a time- and dose-dependent manner. The in vitro angiotensin II effects were abolished by candesartan cilexetil, an inhibitor of the membrane-bound AT1 receptor, and also by actinomycin D, an RNA synthesis inhibitor, and cycloheximide, a protein synthesis inhibitor, indicating that endothelin-1 release depended on AT1 receptor subtype and de novo protein synthesis. Our findings indicate that angiotensin II regulates endothelin-1 release by cultured endothelial cells through an AT1 receptor-dependent pathway, but does not influence circulating endothelin-1 levels in vivo.

The associations of endothelial and podocyte injury in proliferative lupus nephritis: from observational analysis to in vitro study

Lupus ◽  
2019 ◽  
Vol 28 (3) ◽  
pp. 347-358 ◽  
Author(s):  
M Yuan ◽  
Y Tan ◽  
Y Wang ◽  
S X Wang ◽  
F Yu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Injury ◽  
In Vitro Study ◽  
Glomerular Endothelial Cell ◽  
Endothelial Cell Injury ◽  
Endothelin 1 ◽  
Glomerular Endothelial Cells ◽  
Proliferative Lupus Nephritis

Our study aims to evaluate the endothelial cell-podocyte crosstalk in proliferative lupus nephritis (LN). The semi-quantification scores of glomerular endothelial cell injury and the foot process width (FPW) were processed in 110 proliferative LN patients. Podocytes were stimulated with LN-derived IgG. Glomerular endothelial cells were treated with podocyte-conditioned medium (PCM), and then podocytes were incubated with endothelial cell–conditioned medium (ECM). The levels of vascular endothelial growth factor-A (VEGF-A) in PCM and endothelin-1 in ECM were analyzed, and the injury of podocyte and glomerular endothelial cells were further evaluated. The pathological score of glomerular endothelial cell injury was correlated with FPW in LN complicated with thrombotic microangiopathy. In vitro study showed the following: 1. Stimulation of podocytes by IgG from LN led to decline in the expression of nephrin with cytoskeleton rearrangement, and reduction of VEGF-A levels. 2. Exposure of glomerular endothelial cells to PCM incubated with LN-derived IgG (PCM-LN) induced more endothelin-1 secretion and disruption of intercellular tight junction. 3. Exposure of podocytes to ECM stimulated with PCM-LN could induce cytoskeleton redistribution with decrease of nephrin. In conclusion, the pathological glomerular endothelial cell lesions were associated with FPW and the VEGF-endothelin-1 system might play a critical role in the endothelial cell-podocyte crosstalk in LN.

IL-1β alters hemodynamics in newborn intestine: role of endothelin

2006 ◽  
Vol 291 (3) ◽  
pp. G404-G413 ◽  
Author(s):  
Philip T. Nowicki
Keyword(s):  
Endothelial Cells ◽  
Vascular Dysfunction ◽  
Mesenteric Arteries ◽  
Dependent Manner ◽  
Selective Blockade ◽  
Endothelial Nitric Oxide ◽  
Dose Dependent

Studies were carried out to determine the effects of IL-1β on newborn intestinal hemodynamics. IL-1β increased the release of ET-1 by primary endothelial cells in a dose-dependent manner; as well, it reduced expression of the endothelin (ET) type B (ETB) receptor on endothelial cells and increased expression of the ET type A (ETA) receptor on vascular smooth muscle cells. IL-1β increased endothelial cell endothelial nitric oxide (NO) synthase (eNOS) expression but did not enhance eNOS activity as evidenced by release of NOx into conditioned medium in response to acetylcholine or shear stress. The effects of IL-1β on flow-induced dilation were evaluated in terminal mesenteric arteries in vitro. Pretreatment with IL-1β (1 ng; 4 h) significantly attenuated vasodilation in response to flow rates of 100 and 200 μl/min. This effect was mediated, in part, by the endothelin ETA receptor; thus selective blockade of ETA receptors with BQ610 nearly restored flow-induced dilation. In contrast, exogenous ET-1 only shifted the diameter-flow curve downward without altering the percent vasodilation in response to flow. The effects of IL-1β on ileal oxygenation were then studied using in vivo gut loops. Intramesenteric artery infusion of IL-1β upstream of the gut loop caused ileal vasoconstriction and reduced the arterial-venous O2 difference across the gut loop; consequently, it reduced ileal oxygenation by 60%. This effect was significantly attenuated by pretreatment with BQ610. These data support a linkage between the proinflammatory cytokine IL-1β and vascular dysfunction within the intestinal circulation, mediated, at least in part, by the ET system.

Role of Vasopressin Receptor 2 and 3 in ACTH-Secreting Tumors and their Potential Therapeutic Implications

2019 ◽  
Vol 128 (04) ◽  
pp. 263-269
Author(s):  
Jia Yang ◽  
Yehong Yang ◽  
Yongfei Wang ◽  
Shuo Zhang ◽  
Haixia Cheng ◽  
...  
Keyword(s):  
In Vitro Study ◽  
Ectopic Acth Syndrome ◽  
Vasopressin Receptor ◽  
Dependent Manner ◽  
Acth Secretion ◽  
Ectopic Acth ◽  
Therapeutic Implications ◽  
Acth Secreting

Abstract Purpose We investigated the expression of vasopressin receptor 2 and 3 on corticotrophin tumor cells, their role in regulating ACTH secretion, and their potential therapeutic implications. Methods We retrospectively assessed 52 hospitalized patients with pathologically confirmed ACTH-secreting tumors. The expression of vasopressin receptor 2 and 3 was explored via qualitative and quantitative immunohistochemistry analyses. The role of vasopressin receptors in regulating ACTH secretion was further studied in the AtT-20 cell line. Results Among 50 cases of pituitary corticotrophin adenoma, 31 were vasopressin receptor 2 positive, 38 were vasopressin receptor 3 positive, and 24 were both vasopressin receptor 2 and 3 positive. Two patients with ectopic ACTH syndrome were vasopressin receptor 3 positive, and one was also vasopressin receptor 2 positive. In 12 patients who underwent bilateral inferior petrosal sinus sampling before surgery, the central ACTH increment ratio after desmopressin stimulation was correlated with vasopressin receptor 2 but not with vasopressin receptor 3 staining intensity. In an in vitro study, the expression of both vasopressin receptor 2 and 3 on AtT-20 cells was confirmed. The vasopressin receptor 2 antagonist Tolvaptan inhibited desmopressin-induced ACTH secretion in a dose-dependent manner. Conclusions Both vasopressin receptor 2 and 3 are expressed in ACTH-secreting tumors. Vasopressin receptor 2 rather than vasopressin receptor 3 is the primary receptor that seems to mediate the ACTH response in corticotrophin tumors. A vasopressin receptor 2 antagonist can inhibit ACTH secretion induced by desmopressin in AtT-20 cells.

A potential role of TLR2 in xenograft rejection of porcine iliac endothelial cells: An in vitro study

2019 ◽  
Vol 26 (5) ◽  
Author(s):  
Jicheng Chen ◽  
Hanchao Gao ◽  
LinLin Chen ◽  
Xisheng Wang ◽  
Zongpei Song ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Potential Role ◽  
In Vitro Study ◽  
Vitro Study ◽  
Xenograft Rejection

Role of vascular endothelial cells plated on culture dishes and polyurethane patch in inflammation: an in vitro study

1994 ◽  
Vol 109 (1-2) ◽  
pp. 220
Author(s):  
G. Maiwald ◽  
G. Meyer ◽  
A. Walli ◽  
F.W. Schildberg ◽  
D. Seidel
Keyword(s):  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
In Vitro Study ◽  
Vitro Study ◽  
Vascular Endothelial

In vitro responses of ovine intrapulmonary arteries and veins to endothelin-1

1992 ◽  
Vol 263 (1) ◽  
pp. L15-L21 ◽  
Author(s):  
H. Toga ◽  
B. O. Ibe ◽  
J. U. Raj
Keyword(s):  
Age Groups ◽  
Developmental Differences ◽  
Dependent Manner ◽  
H2 Receptor Antagonist ◽  
Endothelin 1 ◽  
Adult Sheep ◽  
Lung Vessels ◽  
Arteries And Veins

We determined responses of third-generation intrapulmonary arteries and veins of fetal, newborn, and adult sheep to endothelin-1 (ET) and the role of endothelium and cyclooxygenase metabolites in ET effects in adult sheep lung vessels. Presence of endothelium in vessel rings was confirmed by response to endothelium-dependent vasodilators, acetylcholine or bradykinin. Vessel tension induced by ET was expressed as a percentage of tension induced by 100 mM KCl. We found that arteries and veins contracted to 10(-9) to 10(-6) M ET in a dose-dependent manner. Veins exhibited greater sensitivity to ET than arteries in all age groups. Arteries and veins of adult sheep lungs were more sensitive to ET than those of fetal and newborn lambs. In adult sheep lung vessels, pretreatment with indomethacin (5 x 10(-6) M) and SQ 29548, a thromboxane A2-prostaglandin H2 receptor antagonist (10(-5) M), significantly attenuated venous contraction to ET; arterial contraction was unaffected. Denuding vessels of endothelium did not affect responses to ET. We conclude that, in ovine lungs, veins are more sensitive to ET than arteries and that developmental differences in pulmonary vascular responses to ET exist.

Unopposed phosphatase action initiates ezrin dysfunction: a potential mechanism for anoxic injury

1997 ◽  
Vol 273 (2) ◽  
pp. C710-C716 ◽  
Author(s):  
J. Chen ◽  
L. J. Mandel
Keyword(s):  
Kinase Inhibitors ◽  
Cell Injury ◽  
Kinase Inhibitor ◽  
In Vitro Study ◽  
Dependent Manner ◽  
Kinase Inhibition ◽  
Anoxic Injury ◽  
First Time

Because extensive kinase inhibition during anoxia has previously been reported, we investigated the role of kinase inhibition in anoxic cell injury by studying the effects of kinase inhibitors on a membrane-microvillar cytoskeleton linker protein, ezrin, in rabbit renal proximal tubules. Like anoxia, kinase inhibitors caused ezrin dephosphorylation in a dose-dependent manner under normoxia. The kinase inhibitor chelerythrine also induced ezrin dissociation from the cytoskeleton, i.e., causing it to lose its membrane-cytoskeleton linker function. Blockage of kinase inhibitor-induced ezrin dephosphorylation by a phosphatase inhibitor, calyculin A, ameliorated ezrin dissociation. Stimulation of the kinase during anoxia did not improve ezrin phosphorylation, suggesting that anoxia-induced kinase inhibition might be due to the lack of the substrate ATP. Finally, in vitro study of ezrin phosphatase revealed no increase in its activity during anoxia, suggesting the principal role of kinase inhibition in the loss of the linker function of ezrin during anoxia. Our results provide, for the first time at the molecular level, a mechanistic insight into anoxic cell injury caused by unopposed phosphatase action.

Pharmacological stimulation of cardiac gap junction coupling does not affect ischemia-induced focal ventricular tachycardia or triggered activity in dogs

2005 ◽  
Vol 288 (2) ◽  
pp. H511-H516 ◽  
Author(s):  
Dezhi Xing ◽  
Anne Louise Kjølbye ◽  
Jørgen S. Petersen ◽  
James B. Martins
Keyword(s):  
Ventricular Tachycardia ◽  
Gap Junction ◽  
Plasma Concentrations ◽  
Three Dimensional ◽  
In Vitro Study ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Triggered Activity

The role of gap junction intercellular communication (GJIC) in ischemia-induced focal ventricular tachycardia (VT) is unknown. We have developed a new, stable antiarrhythmic peptide analog named ZP123 that selectively increases GJIC and prevents reentrant VT. Our aim in this study was to use ZP123 as a tool to assess the role of GJIC on occurrence of ischemia-induced focal VT and triggered activity (TA) due to delayed afterdepolarizations (DADs). Focal VT was induced by programmed stimulation in α-chloralose-anesthetized, open-chest dogs 1–4 h after coronary artery occlusion. Three-dimensional activation mapping was done using 6 bipolar electrograms on each of 23 multipolar needles in the risk zone. Dogs were randomly assigned to receive either saline or ZP123 cumulatively at three dose levels (an intravenous bolus followed by a 30-min infusion per dose). Attempts to induce VT were repeated in each dose. Mass spectrometry was used to measure plasma ZP123 concentrations. Standard microelectrode techniques were used for in vitro study of DADs and TA. Twenty-six dogs with focal VT were included. ZP123 did not affect the inducibility of focal VT at any plasma concentrations vs. saline (0.8 ± 0.1 nM, 77 vs. 75%; 7.8 ± 0.4 nM, 86 vs. 77%; and 78.8 ± 5.0 nM, 77 vs. 91%). In vitro, ZP123 did not affect the induction of DADs (12/12) and TAs (10/10) in ischemic tissues or tissue removed from the origin of focal VT (DADs, 8/8; TAs, 4/4). Therefore, although indirect, the data with the doses and concentrations used suggest that GJIC may not play a major role in the genesis of focal activity in the ischemic models studied.

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