254 research outputs found
Pressure-Induced Upregulation of Preproendothelin-1 and Endothelin B Receptor Expression in Rabbit Jugular Vein In Situ
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Abstract
—Upregulation of endothelin-1 (ET-1) synthesis in venous bypass grafts in response to arterial levels of blood pressure may play a major role in graft failure. To investigate this hypothesis, isolated segments of the rabbit jugular vein were perfused at physiological (0 to 5 mm Hg) and nonphysiological (20 mm Hg) levels of intraluminal pressure. As judged by reverse transcription–polymerase chain reaction analysis (mRNA level), neither endothelin-converting enzyme nor endothelin A receptor expression appeared to be pressure sensitive. In contrast, there was a profound and time-dependent increase in endothelial prepro-ET-1 mRNA and intravascular ET-1 abundance (by ELISA) as well as in smooth muscle endothelin B receptor mRNA and functional protein (by superfusion bioassay) on raising the perfusion pressure from 5 to 20 mm Hg, but not from 0 to 5 mm Hg, for up to 12 hours. Video microscopy analysis revealed that the segments were distended by 75% at 5 mm Hg and near maximally at 20 mm Hg compared with the resting diameter at 0 to 1 mm Hg. Treatment of the segments with actinomycin D (1 μmol/L), the specific protein kinase C inhibitor, Ro 31–8220 (0.1 μmol/L), or the c-Src family–specific tyrosine kinase inhibitor, herbimycin A (0.1 μmol/L), demonstrated that the pressure-induced expression of these gene products occurs at the level of transcription and requires activation of protein kinase C, but not c-Src. In venous bypass grafts such deformation-induced changes in gene expression may contribute not only to acute graft failure through ET-1–induced vasospasm but also to endothelin A receptor– and/or endothelin B receptor–mediated smooth muscle cell hyperplasia and graft occlusion.
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Elevated Perfusion Pressure Upregulates Endothelin-1 and Endothelin B Receptor Expression in the Rabbit Carotid Artery
No full textTo investigate the hypothesis that high blood pressure activates the endothelin system in the vessel wall, isolated segments of the rabbit carotid artery were subjected to different levels of perfusion pressure. Both preproendothelin-l (ppET-1) mRNA abundance and intravascular ET-1 peptide content were strongly upregulated on raising the intraluminal pressure from 90 to 160 mm Hg for 3 to 12 hours, and this increase in ppET-1 mRNA occurred predominantly in the endothelial cells. Endothelin-converting enzyme-1 and endothelin A receptor (ETA-R) expression were pressure-insensitive, whereas that of the ETB-R in the smooth muscle cells was also significantly enhanced. Both the pressure-induced increase in ppET-1 and ETB-R expression required RNA synthesis because they were abolished by actinomycin D. The nuclear signaling mechanisms involved therein, however, appeared to be different. Thus, the pressure-induced expression of ppET-1 and activation of CCAAT-enhancer binding proteins beta and delta were blocked by the tyrosine kinase inhibitor herbimycin A, whereas ETB-R expression and the nuclear translocation of activator protein-1 were abolished by the protein kinase C inhibitor Ro 31-8220. One consequence of these presumably deformation-induced changes in gene expression was an increased rate of apoptosis of the smooth muscle cells in the media that if transferable to the situation in human blood vessels may contribute to hypertension-induced arterial remodeling
Chest Radiography for Diagnosing Acute Respiratory Distress Syndrome—Fishing in the Dark?*
No full textStrengthening Altitude Knowledge: A Delphi Study to Define Minimum Knowledge of Altitude Illness for Laypersons Traveling to High Altitude
No full textInternational audienceBerendsen, Remco R., Peter Bärtsch, Buddha Basnyat, Marc Moritz Berger, Peter Hackett, Andrew M. Luks, Jean-Paul Richalet, Ken Zafren, Bengt Kayser, and the STAK Plenary Group. Strengthening altitude knowledge: a Delphi study to define minimum knowledge of altitude illness for laypersons traveling to high altitude. High Alt Med Biol. 00:000-000, 2022. Introduction: A lack of knowledge among laypersons about the hazards of high-altitude exposure contributes to morbidity and mortality from acute mountain sickness (AMS), high-altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE) among high-altitude travelers. There are guidelines regarding the recognition, prevention, and treatment of acute-altitude illness for experts, but essential knowledge for laypersons traveling to high altitudes has not been defined. We sought expert consensus on the essential knowledge required for people planning to travel to high altitudes. Methods: The Delphi method was used. The panel consisted of two moderators, a core expert group and a plenary expert group. The moderators made a preliminary list of statements defining the desired minimum knowledge for laypersons traveling to high altitudes, based on the relevant literature. These preliminary statements were then reviewed, supplemented, and modified by a core expert group. A list of 33 statements was then presented to a plenary group of experts in successive rounds. Results: It took three rounds to reach a consensus. Of the 10 core experts invited, 7 completed all the rounds. Of the 76 plenary experts, 41 (54%) participated in Round 1, and of these 41 a total of 32 (78%) experts completed all three rounds. The final list contained 28 statements in 5 categories (altitude physiology, sleeping at altitude, AMS, HACE, and HAPE). This list represents an expert consensus on the desired minimum knowledge for laypersons planning high-altitude travel. Conclusion: Using the Delphi method, the STrengthening Altitude Knowledge initiative yielded a set of 28 statements representing essential learning objectives for laypersons who plan to travel to high altitudes. This list could be used to develop educational interventions
On the mechanisms underlying activation and reversal of high altitude-induced pulmonary hypertension in humans - Another piece in the pulmonary puzzle
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The highly dynamic heterochromatin protein Swi6 mediates degradation of heterochromatic transcripts
No full textThe aim of my thesis was to investigate the mechanism of heterochromatin repression mediated by heterochromatin protein Swi6 in S. pombe.
Research over the years challenged the view of heterochromatin as a static and transcriptionally inert structure. Especially in fission yeast it has become clear that heterochromatin silencing requires not only the action of chromatin modifying factors, but also transcriptional activity and RNA degradation processes. Moreover, heterochromatin protein Swi6 was shown to be highly dynamic, unlike what was expected for a protein that is perceived as a major structural component of heterochromatin. Yet, the prevailing model of heterochromatin establishment and spreading is thought to occur by iterative HP1 binding to methylated H3K9 and recruitment of histone methylation activity.
Driven by recent findings in our lab that described a new role for Swi6 in repression and provided a possible explanation for its dynamic behavior, I set out to investigate the mechanism in vivo by studying Swi6 dynamics. Therefore, a major focus of my PhD was to establish a suitable, robust microscopy-based method that allowed me to follow rapid dynamics and produce reliable data. The work I have done challenged the role of Swi6 in heterochromatin maintenance and spreading, but coincides with a clear involvement in sustaining tight repression. While H3K9me levels remained high in the absence of Swi6 and even spread into neighboring regions, heterochromatic transcript levels increased. These observations revealed unanticipated functions for Swi6 and made us reconsider the mechanism of Swi6-mediated silencing. As previously proposed, Swi6 could function as a co-transcriptional checkpoint that mediates RNA degradation (Keller et al., 2012). In this model RNA binds to Swi6 and gets primed for destruction as it is handed over to the RNA decay machinery, involving Cid14 and the exosome or the RNAi machinery. The target specificity depends on the epigenetic make-up of the locus, meaning the recognition of H3K9me by the CD of Swi6, while RNA binding occurs in a sequence independent manner (Keller et al., 2012). Therefore, additional processes that confer specificity, like siRNAs, are needed to ensure correct targeting of H3K9me marks to trigger Swi6-mediated turnover of unwanted RNA transcripts and not of any other random region in the genome
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