Role of endothelin receptors on basal and endothelin-1-stimulated lung myofibroblast proliferationThis article is one of a selection of papers published in the special issue (part 1 of 2) on Forefronts in Endothelin.

2008 ◽  
Vol 86 (6) ◽  
pp. 337-342 ◽  
Author(s):  
Annick Préfontaine ◽  
Angelino Calderone ◽  
Jocelyn Dupuis
Keyword(s):  
Protein Synthesis ◽  
Confocal Imaging ◽  
Receptor Expression ◽  
Leucine Incorporation ◽  
Endothelin 1 ◽  
Selective Blockade ◽  
Dual Blockade ◽  
Lung Remodelling ◽  
Selection Of

Proliferation of myofibroblasts (MYF) contributes to numerous lung disorders. Endothelin-1 (ET-1) production is increased in various lung diseases and could contribute to lung remodelling. The respective roles of ETA and ETB receptors (ETA-R, ETB-R) and the role of endogenous ET-1 production by lung MYF on proliferation of MYF remain uncertain. Rat lung MYF were isolated and 3H-thymidine and 3H-leucine incorporation assays were completed in the presence of a selective ETA-R antagonist, a selective ETB-R antagonist, or a combination of both. Receptor expression was evaluated by confocal imaging, and ET-1 levels were measured by ELISA. Confocal microscopy revealed abundant ETA-R and ETB-R expression on lung MYF. ET-1 (10 nmol/L) stimulated MYF proliferation and protein synthesis through PI3-kinase and p38 pathways. Although neither selective ETA-R blockade (BQ-123, 1 μmol/L) nor selective ETB-R blockade (BQ-788, 1 μmol/L) alone inhibited proliferation or protein synthesis, their combination almost completely abolished ET-1 mitogenic effect. Surprisingly, basal MYF proliferation was increased by selective blockade of either ETA-R or ETB-R alone, but not by dual blockade. ET-1 levels were not affected by the antagonists. Our findings indicate that both the ETA-R and the ETB-R regulate basal and stimulated lung MYF proliferation and suggest possible interactions between the receptors.

scholarly journals Oxidative stress contributes to the enhanced expression of Gqα/PLCβ1 proteins and hypertrophy of VSMC from SHR: role of growth factor receptor transactivation

2016 ◽  
Vol 310 (5) ◽  
pp. H608-H618 ◽  
Author(s):  
Mohammed Emehdi Atef ◽  
Madhu B. Anand-Srivastava
Keyword(s):  
Oxidative Stress ◽  
Protein Synthesis ◽  
Growth Factor ◽  
Cell Volume ◽  
Growth Factor Receptor ◽  
Mapk Signaling ◽  
Confocal Imaging ◽  
Leucine Incorporation ◽  
Enhanced Expression

We showed previously that vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHRs) exhibit overexpression of Gqα/PLCβ1 proteins, which contribute to increased protein synthesis through the activation of MAP kinase signaling. Because oxidative stress has been shown to be increased in hypertension, the present study was undertaken to examine the role of oxidative stress and underlying mechanisms in enhanced expression of Gqα/PLCβ1 proteins and VSMC hypertrophy. Protein expression was determined by Western blotting, whereas protein synthesis and cell volume, markers for VSMC hypertrophy, were determined by [3H]-leucine incorporation and three-dimensional confocal imaging, respectively. The increased expression of Gqα/PLCβ1 proteins, increased protein synthesis, and augmented cell volume exhibited by VSMCs from SHRs were significantly attenuated by antioxidants N-acetyl-cysteine (NAC), a scavenger of superoxide anion, DPI, an inhibitor of NAD(P)H oxidase. In addition, PP2, AG1024, AG1478, and AG1295, inhibitors of c-Src, insulin-like growth factor receptor (IGFR), epidermal growth factor receptor (EGFR), and platelet-derived growth factor receptor (PDGFR), respectively, also attenuated the enhanced expression of Gqα/PLCβ1 proteins and enhanced protein synthesis in VSMCs from SHRs toward control levels. Furthermore, the levels of IGF-1R and EGFR proteins and not of PDGFR were also enhanced in VSMCs from SHRs, which were attenuated significantly by NAC, DPI, and PP2. In addition, NAC, DPI, and PP2 also attenuated the enhanced phosphorylation of IGF-1R, PDGFR, EGFR, c-Src, and EKR1/2 in VSMCs from SHRs. These data suggest that enhanced oxidative stress in VSMCs from SHRs activates c-Src, which through the transactivation of growth factor receptors and MAPK signaling contributes to enhanced expression of Gqα/PLCβ1 proteins and resultant VSMC hypertrophy.

Abstract 15161: Adiponectin Exerts a Protective Role Against Vascular Remodeling During Hypertension

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Crystal M Ghantous ◽  
Sarah Hanache ◽  
Firas Kobaissy ◽  
Asad Zeidan
Keyword(s):  
Protein Synthesis ◽  
Vascular Remodeling ◽  
Mechanical Stretch ◽  
Protective Role ◽  
Leucine Incorporation ◽  
Rat Portal Vein ◽  
Length Relationship ◽  
Longitudinal Orientation ◽  
Ros Formation

Introduction: Hypertension is associated with leptin production and ROS formation in vascular smooth muscle cells (VSMC) and contributes to vascular remodeling. Adiponectin (ADQ) has a cardioprotective role on the heart, but the protective role of ADQ on VSMC during hypertension has not been fully elucidated yet. Hypothesis: Mechanical stretch/hypertension is associated with a low ADQ/leptin ratio in VSMC, leading to VSMC remodeling. Methods: To mimic hypertension, the rat portal vein was cultured either mechanically stretched with 1.2 gram weights (due to the force-length relationship normalized to the human force of stretch during hypertension and the longitudinal orientation of its VSMC) or left unstretched. ADQ, leptin, eNOS, p-ERK1/2 and p-AKT expression in VSMC was evaluated by Western blot. The protective effect of adiponectin (5-10 μg/ml; 15 min-24 hr) was investigated on ROS formation by DHE staining and on hypertrophy by protein synthesis via [ 3 H]leucine incorporation. Results: Mechanical stretch for 24 hr reduced the expression of ADQ in VSMC (0.49 ± 0.08 fold, n=6, p<0.05) and increased leptin (2.51 ± 0.39 fold, n=6, p<0.05) compared to controls. Stretch (24 hr) decreased ADQ mRNA expression by 0.31 ± 0.11 fold (n=7, p<0.05) and ADQ receptor R2 by 0.51 ± 0.21 fold (n=7, p<0.05) but had no effect on ADQ receptor R1 (n=8). This effect of stretch was associated with increased protein synthesis by 1.39 ± 0.06 fold (n=6, p<0.05), while exogenous ADQ significantly inhibited stretch-induced hypertrophy (n=6, p<0.05). Stretch (15 min) increased p-ERK1/2 and p-AKT by 2.10 ± 0.25 and 4.03 ± 0.61 fold respectively (n=5, p<0.05), but ADQ reduced p-ERK1/2 and p-AKT by 0.82 ± 0.26 and 0.55 ± 0.25 fold respectively (n=3, p<0.05) in stretched vessels. eNOS expression decreased by 0.70 ± 0.06 fold (n=5, p<0.05) after stretch for 24 hr, while ADQ increased eNOS in stretched veins by 2.02 ± 0.41 fold (n=3, p<0.05). Stretch for 1 hr increased ROS by 5.69 ± 0.13 fold (n=3, p<0.05), whereas ADQ significantly inhibited ROS in stretched vessels (1.71 ± 0.22 fold, n=3). Conclusion: Mechanical stretch reduces the ADQ/leptin ratio in VSMC. ADQ plays a protective role against vascular remodeling during hypertension by affecting eNOS, ERK, AKT, ROS and hypertrophy.

scholarly journals Evidence for the Involvement of Type I Interferon in Pulmonary Arterial Hypertension

2014 ◽  
Vol 114 (4) ◽  
pp. 677-688 ◽  
Author(s):  
Peter M. George ◽  
Eduardo Oliver ◽  
Peter Dorfmuller ◽  
Olivier D. Dubois ◽  
Daniel M. Reed ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Receptor Expression ◽  
Type I ◽  
Type I Ifn ◽  
Endothelin 1 ◽  
Gene And Protein Expression ◽  
Pulmonary Arterial

Rationale : Evidence is increasing of a link between interferon (IFN) and pulmonary arterial hypertension (PAH). Conditions with chronically elevated endogenous IFNs such as systemic sclerosis are strongly associated with PAH. Furthermore, therapeutic use of type I IFN is associated with PAH. This was recognized at the 2013 World Symposium on Pulmonary Hypertension where the urgent need for research into this was highlighted. Objective : To explore the role of type I IFN in PAH. Methods and Results : Cells were cultured using standard approaches. Cytokines were measured by ELISA. Gene and protein expression were measured using reverse transcriptase polymerase chain reaction, Western blotting, and immunohistochemistry. The role of type I IFN in PAH in vivo was determined using type I IFN receptor knockout (IFNAR1 −/− ) mice. Human lung cells responded to types I and II but not III IFN correlating with relevant receptor expression. Type I, II, and III IFN levels were elevated in serum of patients with systemic sclerosis associated PAH. Serum interferon γ inducible protein 10 (IP10; CXCL10) and endothelin 1 were raised and strongly correlated together. IP10 correlated positively with pulmonary hemodynamics and serum brain natriuretic peptide and negatively with 6-minute walk test and cardiac index. Endothelial cells grown out of the blood of PAH patients were more sensitive to the effects of type I IFN than cells from healthy donors. PAH lung demonstrated increased IFNAR1 protein levels. IFNAR1 −/− mice were protected from the effects of hypoxia on the right heart, vascular remodeling, and raised serum endothelin 1 levels. Conclusions : These data indicate that type I IFN, via an action of IFNAR1, mediates PAH.

scholarly journals Glycemic control prevents microvascular remodeling and increased tone in Type 2 diabetes: link to endothelin-1

2009 ◽  
Vol 296 (4) ◽  
pp. R952-R959 ◽  
Author(s):  
Kamakshi Sachidanandam ◽  
Jim R. Hutchinson ◽  
Mostafa M. Elgebaly ◽  
Erin M. Mezzetti ◽  
Anne M. Dorrance ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glycemic Control ◽  
Receptor Expression ◽  
Myogenic Tone ◽  
Resistance Arteries ◽  
Gk Rats ◽  
Endothelin 1 ◽  
Vascular Compliance

Medial thickening and vascular hypertrophy of resistance arteries can lead to cardiovascular complications associated with diabetes. While previous studies have established a role of Type 1 diabetes in vascular remodeling, we recently extended these observations to Type 2 diabetes and reported increased collagen deposition due to alterations in matrix metalloproteinase expression and activity in mesenteric resistance arteries. These studies also showed that remodeling response was mediated by endothelin-1 (ET-1) via activation of ETA receptors, whereas blockade of ETB receptors exacerbated the remodeling. However, the effectiveness of glycemic control strategies in preventing these vascular changes, including activation of the ET system still remained unclear. Also, very little is known about whether and to what extent reorganization of the extracellular matrix (ECM) affects vascular compliance and vasomotor tone. Accordingly, this study assessed structural remodeling of mesenteric microvessels, vascular compliance, and myogenic tone, as well as the role of matrix metalloproteinases (MMP) in mediating these processes. Spontaneously diabetic, non-obese Goto-Kakizaki (GK) rats, a model for Type 2 diabetes, and normoglycemic Wistar rats were used for the studies. A subset of GK rats were administered metformin to achieve euglycemia. Glycemic control normalized the increased media-to-lumen ratios (M/L) and myogenic tone seen in diabetes, as well as normalizing plasma ET-1 levels and mesenteric ETA receptor expression. There was increased collagen synthesis in diabetes paralleled by decreased collagenase MMP-13 activity, while glycemic control attenuated the process. These findings and our previous study taken together suggest that hyperglycemia-mediated activation of ET-1 and ETA receptors alter vascular structure and mechanics in Type 2 diabetes.

Inhibition of glucose metabolism by progesterone in adipocytes: role of protein synthesis

1991 ◽  
Vol 69 (12) ◽  
pp. 1861-1867 ◽  
Author(s):  
P. Cordoba ◽  
A. Kaaya ◽  
O. Richard ◽  
M.-Th. Sutter-Dub
Keyword(s):  
Protein Synthesis ◽  
Glucose Metabolism ◽  
Glucose Transport ◽  
Glucose Oxidation ◽  
Actinomycin D ◽  
Inhibitory Effect ◽  
Leucine Incorporation ◽  
Female Rat ◽  
Sds Page

Progesterone decreases [1-14C]glucose oxidation in isolated female rat adipocytes within 20 min of incubation. Because steroids regulate transcription mechanisms, the relationship between protein synthesis and glucose metabolism was studied in the presence of progesterone. Actinomycin D does not affect basal glucose oxidation or the progesterone effects on it; cycloheximide and puromycin decrease basal glucose oxidation, but only puromycin decreases the inhibitory progesterone effect. Although puromycin inhibits glucose transport, the common site of action of puromycin and progesterone does not seem to be glucose transport, which, as we showed previously, is not modified by the steroid. Incorporation of [3H]leucine into acid-precipitable proteins is decreased by puromycin and cycloheximide but not by actinomycin D or progesterone; moreover, the action of these inhibitors does not change in the presence of the steroid. As shown by electrophoresis (SDS–PAGE) and autoradiography, L-leucine is incorporated into adipocyte proteins as early as 20 min and progesterone increases this incorporation into five proteins. Leucine is a ketogenic amino acid that is also incorporated into lipids; progesterone depresses L-leucine incorporation into fatty acids by a glucose-dependent mechanism. These results suggest that the inhibitory effect of progesterone on glucose metabolism is related to an enhanced protein synthesis counterbalanced by decreased fatty acid synthesis.Key words: adipocytes, glucose metabolism, progesterone, protein synthesis, gel autoradiography.

Faculty selection of textbooks: Key variables and the role of teaching experience

2010 ◽  
Author(s):  
Aja Taitano ◽  
Bradley Smith ◽  
Cade Hulbert ◽  
Kristin Batten ◽  
Lalania Woodstrom ◽  
...  
Keyword(s):  
Teaching Experience ◽  
Key Variables ◽  
Faculty Selection ◽  
Selection Of

Posttransplant CMV infection and the role of immunosuppression (Sponsor: Novartis Pharma GmbH, Nürnberg)

2016 ◽  
Vol 04 (01) ◽  
pp. 4-10
Keyword(s):  
Lower Incidence ◽  
Paradigm Shift ◽  
Mtor Inhibitor ◽  
De Novo ◽  
Expert Panel ◽  
Risk Of Infection ◽  
Cmv Infection ◽  
Expert Meeting ◽  
Selection Of

AbstractImmunosuppression permits graft survival after transplantation and consequently a longer and better life. On the other hand, it increases the risk of infection, for instance with cytomegalovirus (CMV). However, the various available immunosuppressive therapies differ in this regard. One of the first clinical trials using de novo everolimus after kidney transplantation [1] already revealed a considerably lower incidence of CMV infection in the everolimus arms than in the mycophenolate mofetil (MMF) arm. This result was repeatedly confirmed in later studies [2–4]. Everolimus is now considered a substance with antiviral properties. This article is based on the expert meeting “Posttransplant CMV infection and the role of immunosuppression”. The expert panel called for a paradigm shift: In a CMV prevention strategy the targeted selection of the immunosuppressive therapy is also a key element. For patients with elevated risk of CMV, mTOR inhibitor-based immunosuppression is advantageous as it is associated with a significantly lower incidence of CMV events.

The role of surfactant protein D in fibrotic lung remodelling

Pneumologie ◽  
2014 ◽  
Vol 68 (06) ◽  
Author(s):  
J Viereck ◽  
L Knudsen ◽  
JP Schneider ◽  
M Ochs ◽  
T Thum
Keyword(s):  
Surfactant Protein ◽  
Surfactant Protein D ◽  
Lung Remodelling
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