scholarly journals Protease-Activated Receptor PAR-4: An Inducible Switch between Thrombosis and Vascular Inflammation?

2017 ◽  
Vol 117 (11) ◽  
pp. 2013-2025 ◽  
Author(s):  
Anke Fender ◽  
Bernhard Rauch ◽  
Tobias Geisler ◽  
Karsten Schrör
Keyword(s):  
Vascular Inflammation ◽  
Cellular Growth ◽  
Transcriptional Level ◽  
Redox Stress ◽  
Promising Target ◽  
Cardiovascular Patients ◽  
Independent Functions ◽  
Sphingosine 1 Phosphate ◽  
Protease Activated Receptor 1

AbstractThrombin triggers activation of platelets through protease-activated receptor 1 (PAR-1) and PAR-4. Both receptors are widely expressed and exert multiple platelet-independent functions. PAR signalling contributes to healing responses after injury, by promoting cytokine activity and cellular growth and mobility. Uncontrolled PAR activation, however, can prevent timely resolution of inflammation, enhance thrombogenic endothelial function and drive adverse remodelling. The specific role of PAR-4 in thromboinflammatory vascular disease has been largely underestimated, given the relatively limited expression of PAR-4 in non-platelet cells under healthy conditions. However, unlike PAR-1, PAR-4 expression adapts dynamically to numerous stimuli associated with thromboinflammation, including thrombin, angiotensin II, sphingosine-1-phosphate (S1P), high glucose and redox stress, suggesting expression is switched on ‘at need’. Prostacyclin negatively regulates PAR-4 expression at the post-transcriptional level, which may serve to fine-tune thrombin responses and limit these to the injury site. PAR-4 elicits inflammatory, mitogenic and proliferative actions not only in response to thrombin but also to numerous other inflammatory proteases, and can cross-talk with other receptor systems such as S1P and adenosine receptors. Accordingly, PAR-4 has emerged as a candidate player in vessel disease and cardiac post-infarction remodelling. Currently, PAR-4 is a particularly promising target for safer anti-thrombotic therapies. Recent studies with the PAR-4 antagonist BMS-986120 lend support to the concept that selective antagonism of PAR-4 may offer both an effective and safe anti-thrombotic therapy in the acute thrombotic setting as well as an anti-inflammatory strategy to prevent long-term progressive atherosclerotic disease in high-risk cardiovascular patients.

scholarly journals Neonatal HDL Counteracts Placental Vascular Inflammation via S1P–S1PR1 Axis

2020 ◽  
Vol 21 (3) ◽  
pp. 789
Author(s):  
Ilaria Del Gaudio ◽  
Sebastian Hendrix ◽  
Christina Christoffersen ◽  
Christian Wadsack
Keyword(s):  
Vascular Inflammation ◽  
Density Lipoprotein ◽  
Adverse Outcomes ◽  
Vascular Protection ◽  
Protective Function ◽  
Arterial Endothelial Cell ◽  
Sphingosine 1 Phosphate ◽  
Placental Inflammation ◽  
Short And Long Term

Placental inflammation and dysfunction during pregnancy are associated with short- and long-term adverse outcomes for the offspring. However, the mechanisms of vascular protection at the feto-placental interface are still poorly investigated. The high-density lipoprotein (HDL) associated sphingosine-1-phosphate (S1P) has been described as a powerful anti-inflammatory complex. This study aimed to elucidate the role of cord blood-derived HDL (nHDL) in feto-placental endothelial dysfunction. Here, we report that the exposure of primary fetal placental arterial endothelial cell (fPAEC) to healthy nHDL-S1P attenuated the ability of TNFα to activate NF-κB signaling and increase the expression of pro-inflammatory markers. Moreover, the angiotensin II (AngII)-induced reactive oxygen species (ROS) production was blunted in the presence of nHDL, whereas it was preserved when the cells were preincubated with S1P receptor antagonists, suggesting that S1P accounts for the vascular protective function of nHDL at the feto-placental unit. These results highlight the importance of HDL and S1P metabolism and signaling in pregnancy pathophysiology.

CARP Plays a Key Role in Cellular Growth Under Hypertrophic Stimuli in Neonatal Rat Ventricular Myocytes

2013 ◽  
Vol 9 ◽  
Author(s):  
Tara A Shrout
Keyword(s):  
Gene Expression ◽  
Ventricular Myocytes ◽  
Cellular Growth ◽  
Neonatal Rat ◽  
Transcriptional Level ◽  
Dual Nature ◽  
Hypertrophic Growth ◽  
Rat Ventricular Myocytes ◽  
Neonatal Rat Ventricular Myocytes ◽  
Over Time

Cardiac hypertrophy is a growth process that occurs in response to stress stimuli or injury, and leads to the induction of several pathways to alter gene expression. Under hypertrophic stimuli, sarcomeric structure is disrupted, both as a consequence of gene expression and local changes in sarcomeric proteins. Cardiac-restricted ankyrin repeat protein (CARP) is one such protein that function both in cardiac sarcomeres and at the transcriptional level. We postulate that due to this dual nature, CARP plays a key role in maintaining the cardiac sarcomere. GATA4 is another protein detected in cardiomyocytes as important in hypertrophy, as it is activated by hypertrophic stimuli, and directly binds to DNA to alter gene expression. Results of GATA4 activation over time were inconclusive; however, the role of CARP in mediating hypertrophic growth in cardiomyocytes was clearly demonstrated. In this study, Neonatal Rat Ventricular Myocytes were used as a model to detect changes over time in CARP and GATA4 under hypertrophic stimulation by phenylephrine and high serum media. Results were detected by analysis of immunoblotting. The specific role that CARP plays in mediating cellular growth under hypertrophic stimuli was studied through immunofluorescence, which demonstrated that cardiomyocyte growth with hypertrophic stimulation was significantly blunted when NRVMs were co-treated with CARP siRNA. These data suggest that CARP plays an important role in the hypertrophic response in cardiomyocytes.

scholarly journals Impact of the COVID-19 pandemic: a perspective from industry

2020 ◽  
Vol 22 (Supplement_P) ◽  
pp. P56-P59
Author(s):  
Nick E J West ◽  
Wai-Fung Cheong ◽  
Els Boone ◽  
Neil E Moat
Keyword(s):  
Care Delivery ◽  
Models Of Care ◽  
Medium Term ◽  
Change Models ◽  
New Device ◽  
Supply Chain Logistics ◽  
Cardiovascular Patients ◽  
Medical Crisis ◽  
Device Industry

Abstract The global COVID-19 pandemic has led to unprecedented change throughout society.1 As the articles in this supplement outline, all segments of the broader cardiovascular community have been forced to adapt, to change models of care delivery, and to evolve and innovate in order to deliver optimal management for cardiovascular patients. The medtech/device industry has not been exempt from such change and has been forced to navigate direct and indirect COVID-associated disruption, with effects felt from supply chain logistics to the entire product lifecycle, from the running of clinical trials to new device approvals and managing training, proctoring and congresses in an increasingly-online world. This sea-change in circumstances itself has enforced the industry, in effect, to disrupt its own processes, models and activities. Whilst some of these changes may be temporary, many will endure for some time and some will doubtless become permanent; one thing is for sure: the healthcare ecosystem, including the medical device industry, will never look quite the same again. Although the pandemic has brought a short- to medium-term medical crisis to many countries, its role as a powerful disruptor cannot be underestimated, and may indeed prove to be a force for long-term good, given the accelerated innovation and rapid adaptation that it has cultivated.

scholarly journals The Endothelial Glycocalyx as a Target of Ischemia and Reperfusion Injury in Kidney Transplantation—Where Have We Gone So Far?

2021 ◽  
Vol 22 (4) ◽  
pp. 2157
Author(s):  
Anila Duni ◽  
Vassilios Liakopoulos ◽  
Vasileios Koutlas ◽  
Charalampos Pappas ◽  
Michalis Mitsis ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Reperfusion Injury ◽  
Heparan Sulphate ◽  
Graft Function ◽  
Endothelial Permeability ◽  
Endothelial Glycocalyx ◽  
Ischemia And Reperfusion Injury ◽  
New Era ◽  
Sphingosine 1 Phosphate

The damage of the endothelial glycocalyx as a consequence of ischemia and/or reperfusion injury (IRI) following kidney transplantation has come at the spotlight of research due to potential associations with delayed graft function, acute rejection as well as long-term allograft dysfunction. The disintegration of the endothelial glycocalyx induced by IRI is the crucial event which exposes the denuded endothelial cells to further inflammatory and oxidative damage. The aim of our review is to present the currently available data regarding complex links between shedding of the glycocalyx components, like syndecan-1, hyaluronan, heparan sulphate, and CD44 with the activation of intricate immune system responses, including toll-like receptors, cytokines and pro-inflammatory transcription factors. Evidence on modes of protection of the endothelial glycocalyx and subsequently maintenance of endothelial permeability as well as novel nephroprotective molecules such as sphingosine-1 phosphate (S1P), are also depicted. Although advances in technology are making the visualization and the analysis of the endothelial glycocalyx possible, currently available evidence is mostly experimental. Ongoing progress in understanding the complex impact of IRI on the endothelial glycocalyx, opens up a new era of research in the field of organ transplantation and clinical studies are of utmost importance for the future.

Involvement of proteinase activated receptor-2in the vascular response to sphingosine 1-phosphate

2013 ◽  
Vol 126 (8) ◽  
pp. 545-556 ◽  
Author(s):  
Fiorentina Roviezzo ◽  
Antonella De Angelis ◽  
Luana De Gruttola ◽  
Antonio Bertolino ◽  
Nikol Sullo ◽  
...  
Keyword(s):  
Vascular Inflammation ◽  
Vascular Response ◽  
Vascular Effect ◽  
Vascular Responses ◽  
Sphingosine 1 Phosphate

S1P exerts a diverse set of vascular responses, and PAR-2 has been shown to be involved in vascular inflammation as well as in other inflammatory-based diseases. In the present study, we demonstrate that S1P-mediated vascular effect involves PAR-2 activation.

scholarly journals Activation of the receptor tyrosine kinase RET improves long-term hematopoietic stem cell outgrowth and potency

Blood ◽  
2020 ◽  
Vol 136 (22) ◽  
pp. 2535-2547 ◽  
Author(s):  
W. Grey ◽  
R. Chauhan ◽  
M. Piganeau ◽  
H. Huerga Encabo ◽  
M. Garcia-Albornoz ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Culture Conditions ◽  
Cellular Growth ◽  
Great Promise ◽  
Bone Marrow Niche ◽  
Hematopoietic Stem ◽  
Intracellular Signaling Pathway ◽  
Wide Range

Abstract Expansion of human hematopoietic stem cells (HSCs) is a rapidly advancing field showing great promise for clinical applications. Recent evidence has implicated the nervous system and glial family ligands (GFLs) as potential drivers of hematopoietic survival and self-renewal in the bone marrow niche; how to apply this process to HSC maintenance and expansion has yet to be explored. We show a role for the GFL receptor, RET, at the cell surface of HSCs in mediating sustained cellular growth, resistance to stress, and improved cell survival throughout in vitro expansion. HSCs treated with the key RET ligand/coreceptor complex, glial-derived neurotrophic factor and its coreceptor, exhibit improved progenitor function at primary transplantation and improved long-term HSC function at secondary transplantation. Finally, we show that RET drives a multifaceted intracellular signaling pathway, including key signaling intermediates protein kinase B, extracellular signal-regulated kinase 1/2, NF-κB, and p53, responsible for a wide range of cellular and genetic responses that improve cell growth and survival under culture conditions.

scholarly journals Age Dependendent Efficacy of Ace Inhibitors Among Chinese Cardiovascular Patients During Hospitalization Phase

2011 ◽  
Vol 1 (2) ◽  
pp. 59-63
Author(s):  
Tabish Hussain ◽  
Li Yu Shu ◽  
A Seid Adji ◽  
Tumenjavkhlan Sosorburam
Keyword(s):  
Myocardial Infarction ◽  
Elderly Patients ◽  
Ace Inhibitors ◽  
Ace Inhibitor ◽  
Recovery Period ◽  
Control Group ◽  
Study Group ◽  
Significant Finding ◽  
Cardiovascular Patients

Objective: Cardiac failure is a global burden among cardiovascular diseases, and major cause of morbidity and mortality especially among elderly age group. Angiotensin Converting Enzyme(ACE) inhibitors, remained the choice of treatment as they inhibit the renin angiotensin aldosterone system along with reduction in levels of pro-inflammatory cytokines, both of them are key factors in progression and complications of heart failure. The aim of this study was to rule out the effect of aging and efficacy of ACE inhibitor, Captopril, among Chinese cardiovascular patients with acute myocardial infarction (MI) during the hospitalization phase of therapy. Material & Methods: Randomized control trial at hospital of Tongji Medical College Wuhan, China over a period of more than 1 year from April 2009 till July 2010 recruiting patients in two stages. A total of 260 patients with mean age 65±8 years were recruited. All suffered from first time myocardial infarction and arrived in Cardiac emergency within 72 hours of the event. The participants were then randomly divided in study and control groups which were then further classified in sub-groups depending upon their age. Study group received ACE inhibitor Captopril in addition to standardized therapy while control group just received the conventional therapy for the event. Statistical analyses were done to formulate the corre-lation between multi-variables. Results: Participants were divided in Study group (N=150) (A and C, Young and Old) and the control group (N=110) (B and D, Young and Old). Survival rate was better among elderly on captopril in comparison to younger ones during the hospitalization. The Systolic blood pressure among study group was significantly lower than control group (132.9±16.3mmHg/84.7 ±9.1mmHg vs. 147.1±17.4mmHg/85.1 ±10.9mmHg, P<0.05).Patient’s survival was statistically significant with respect to age (P<0.001). Conclusion: Treatment with Captopril is definitely associated with improved short as well as long term cardiac prognosis and markedly. Captopril therapy is associated with improved long term prognosis and reduced cardiac mortality during the hospitalization phase of the therapy and recovery period. But the most significant finding is that the increased survival after taking Captopril was higher in elderly patients than in younger patients. ACE inhibitors like Captopril in proper dosage play a real vital beneficial role among elderly patients as compared to the younger ones, but still there is need to recruit a large cohort in different ethnic groups with different genetic makeup. Key Words: Myocardial infarction (MI); Ace-inhibitor; Aging DOI: 10.3126/ajms.v1i2.2947Asian Journal of Medical Sciences 1 (2010) 59-63

scholarly journals Effects of Ionizing Radiation and Long-Term Storage on Hydrated vs. Dried Cell Samples of Extremophilic Microorganisms

2022 ◽  
Vol 10 (1) ◽  
pp. 190
Author(s):  
Ida Romano ◽  
Carlo Camerlingo ◽  
Lisa Vaccari ◽  
Giovanni Birarda ◽  
Annarita Poli ◽  
...  
Keyword(s):  
Ionizing Radiation ◽  
Galactic Cosmic Rays ◽  
Cellular Growth ◽  
Space Environment ◽  
Water Medium ◽  
Space Condition ◽  
Long Term Storage ◽  
Extremophilic Microorganisms ◽  
Term Storage

A main factor hampering life in space is represented by high atomic number nuclei and energy (HZE) ions that constitute about 1% of the galactic cosmic rays. In the frame of the “STARLIFE” project, we accessed the Heavy Ion Medical Accelerator (HIMAC) facility of the National Institute of Radiological Sciences (NIRS) in Chiba, Japan. By means of this facility, the extremophilic species Haloterrigena hispanica and Parageobacillus thermantarcticus were irradiated with high LET ions (i.e., Fe, Ar, and He ions) at doses corresponding to long permanence in the space environment. The survivability of HZE-treated cells depended upon either the storage time and the hydration state during irradiation; indeed, dry samples were shown to be more resistant than hydrated ones. With particular regard to spores of the species P. thermantarcticus, they were the most resistant to irradiation in a water medium: an analysis of the changes in their biochemical fingerprinting during irradiation showed that, below the survivability threshold, the spores undergo to a germination-like process, while for higher doses, inactivation takes place as a consequence of the concomitant release of the core’s content and a loss of integrity of the main cellular components. Overall, the results reported here suggest that the selected extremophilic microorganisms could serve as biological model for space simulation and/or real space condition exposure, since they showed good resistance to ionizing radiation exposure and were able to resume cellular growth after long-term storage.

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