scholarly journals Dual Role of Thrombospondin-1 in Flow-Induced Remodeling

2021 ◽  
Vol 22 (21) ◽  
pp. 12086
Author(s):  
Céline Grenier ◽  
Antoine Caillon ◽  
Mathilde Munier ◽  
Linda Grimaud ◽  
Tristan Champin ◽  
...  
Keyword(s):  
Blood Flow ◽  
Immune Cell ◽  
Ex Vivo ◽  
Mesenteric Arteries ◽  
Intraluminal Pressure ◽  
Neutrophil Accumulation ◽  
Surface Receptors ◽  
Thrombospondin 1

(1) Background: Chronic increases in blood flow, as in cardiovascular diseases, induce outward arterial remodeling. Thrombospondin-1 (TSP-1) is known to interact with matrix proteins and immune cell-surface receptors, but its contribution to flow-mediated remodeling in the microcirculation remains unknown. (2) Methods: Mesenteric arteries were ligated in vivo to generate high- (HF) and normal-flow (NF) arteries in wild-type (WT) and TSP-1-deleted mice (TSP-1−/−). After 7 days, arteries were isolated and studied ex vivo. (3) Results: Chronic increases in blood flow induced outward remodeling in WT mice (increasing diameter from 221 ± 10 to 280 ± 10 µm with 75 mmHg intraluminal pressure) without significant effect in TSP-1−/− (296 ± 18 to 303 ± 14 µm), neutropenic or adoptive bone marrow transfer mice. Four days after ligature, pro inflammatory gene expression levels (CD68, Cox2, Gp91phox, p47phox and p22phox) increased in WT HF arteries but not in TSP-1−/− mice. Perivascular neutrophil accumulation at day 4 was significantly lower in TSP-1−/− than in WT mice. (4) Conclusions: TSP-1 origin is important; indeed, circulating TSP-1 participates in vasodilation, whereas both circulating and tissue TSP-1 are involved in arterial wall thickness and diameter expansion.

scholarly journals ET-CORM Mediated Vasorelaxation of Small Mesenteric Arteries: Involvement of Kv7 Potassium Channels

2021 ◽  
Vol 12 ◽  
Author(s):  
Danfeng Zhang ◽  
Bernhard M. Krause ◽  
Hans-Günther Schmalz ◽  
Paulus Wohlfart ◽  
Benito A. Yard ◽  
...  
Keyword(s):  
Soluble Guanylate Cyclase ◽  
Ex Vivo ◽  
Peripheral Resistance ◽  
Mesenteric Arteries ◽  
Kv7 Channels ◽  
Pre Treatment ◽  
Functional Relevance ◽  
Potential Use

Although the vasoactive properties of carbon monoxide (CO) have been extensively studied, the mechanism by which CO mediates vasodilation is not completely understood. Through-out published studies on CO mediated vasodilation there is inconsistency on the type of K+-channels that are activated by CO releasing molecules (CORMs). Since the vasorelaxation properties of enzyme triggered CORMs (ET-CORMs) have not been studied thus far, we first assessed if ET-CORMs can mediate vasodilation of small mesenteric arteries and subsequently addressed the role of soluble guanylate cyclase (sGC) and that of K-channels herein. To this end, 3 different types of ET-CORMs that either contain acetate (rac-1 and rac-4) or pivalate (rac-8) as ester functionality, were tested ex vivo on methoxamine pre-contracted small rat mesenteric arteries in a myograph setting. Pre-contracted mesenteric arteries strongly dilated upon treatment with both types of acetate containing ET-CORMs (rac-1 and rac-4), while treatment with the pivalate containing ET-CORM (rac-8) resulted in no vasodilation. Pre-treatment of mesenteric arteries with the sGC inhibitor ODQ abolished rac-4 mediated vasodilation, similar as for the known sGC activator SNP. Likewise, rac-4 mediated vasodilation did not occur in KCL pretreated mesenteric arteries. Although mesenteric arteries abundantly expressed a variety of K+-channels only Kv7 channels were found to be of functional relevance for rac-4 mediated vasodilation. In conclusion the current results identified Kv7 channels as the main channel by which rac-4 mediates vasodilation. In keeping with the central role of Kv7 in the control of vascular tone and peripheral resistance these promising ex-vivo data warrant further in vivo studies, particularly in models of primary hypertension or cardiac diseases, to assess the potential use of ET-CORMs in these diseases.

Attenuation of immune-mediated glomerulonephritis with an anti-CD11b monoclonal antibody

1993 ◽  
Vol 264 (4) ◽  
pp. F715-F721 ◽  
Author(s):  
X. Wu ◽  
J. Pippin ◽  
J. B. Lefkowith
Keyword(s):  
Monoclonal Antibody ◽  
Ex Vivo ◽  
Neutrophil Migration ◽  
Surface Receptors ◽  
Eicosanoid Production ◽  
Immune Mediated ◽  
Disease Induction ◽  
Peripheral Leukocytes

Nephrotoxic nephritis (NTN), a model of autoimmune glomerulonephritis, is characterized by glomerular inflammation, which results in both proteinuria and an increase in eicosanoid production. In light of the ability of CD18 integrins to participate in leukocyte adherence (and thereby migration), we examined the role of the integrin CD11b/CD18 in NTN using OX42, a monoclonal antibody directed against rat CD11b. Administration of OX42 30 min before induction of NTN decreased proteinuria (by 50%) but did not affect the number of leukocytes found in the glomerulus or the accompanying increase in glomerular eicosanoid production. Administration of OX42 16 h before disease induction led to a more substantial decrease in proteinuria (80%) and, in contrast to 30 min pretreatment, decreased the number of neutrophils found in the glomerulus and the accompanying increase in glomerular eicosanoid production (both by 50%). OX42 pretreatment had no effect on the number of macrophages found in glomeruli. Circulating leukocytes from animals treated with OX42 in vivo showed saturating surface levels of antibody by fluorescence-activated cell sorting (FACS) analysis and normal upregulation of CD11b by pharmacological activation. Sixteen hours after in vivo injection of OX42, 50% more peripheral leukocytes were labeled relative to control leukocytes labeled with OX42 ex vivo. Glomerular leukocytes in NTN exhibited upregulated expression of CD11b relative to peripheral leukocytes. These data show that CD11b/CD18 may participate in the acute expression of glomerular damage in NTN in a fashion not wholly dependent on blocking neutrophil migration into glomeruli. Blockade of surface receptors (as opposed to inhibition of upregulation) is sufficient to obtain this effect.

The Role of Polyphenols in the Modulation of Plasma Non-Enzymatic Antioxidant Capacity (NEAC)

2012 ◽  
Vol 82 (3) ◽  
pp. 228-232 ◽  
Author(s):  
Mauro Serafini ◽  
Giuseppa Morabito
Keyword(s):  
Antioxidant Capacity ◽  
Dietary Intervention ◽  
Ex Vivo ◽  
The Body ◽  
Dietary Polyphenols ◽  
Enzymatic Antioxidant ◽  
Endogenous Antioxidant

Dietary polyphenols have been shown to scavenge free radicals, modulating cellular redox transcription factors in different in vitro and ex vivo models. Dietary intervention studies have shown that consumption of plant foods modulates plasma Non-Enzymatic Antioxidant Capacity (NEAC), a biomarker of the endogenous antioxidant network, in human subjects. However, the identification of the molecules responsible for this effect are yet to be obtained and evidences of an antioxidant in vivo action of polyphenols are conflicting. There is a clear discrepancy between polyphenols (PP) concentration in body fluids and the extent of increase of plasma NEAC. The low degree of absorption and the extensive metabolism of PP within the body have raised questions about their contribution to the endogenous antioxidant network. This work will discuss the role of polyphenols from galenic preparation, food extracts, and selected dietary sources as modulators of plasma NEAC in humans.

scholarly journals Heparan sulfate and heparin interactions with proteins

2015 ◽  
Vol 12 (110) ◽  
pp. 20150589 ◽  
Author(s):  
Maria C. Z. Meneghetti ◽  
Ashley J. Hughes ◽  
Timothy R. Rudd ◽  
Helena B. Nader ◽  
Andrew K. Powell ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Ex Vivo ◽  
Sequence Specificity ◽  
Structure Activity ◽  
Multiple Binding Sites ◽  
Multiple Binding ◽  
Heparin Activity

Heparan sulfate (HS) polysaccharides are ubiquitous components of the cell surface and extracellular matrix of all multicellular animals, whereas heparin is present within mast cells and can be viewed as a more sulfated, tissue-specific, HS variant. HS and heparin regulate biological processes through interactions with a large repertoire of proteins. Owing to these interactions and diverse effects observed during in vitro , ex vivo and in vivo experiments, manifold biological/pharmacological activities have been attributed to them. The properties that have been thought to bestow protein binding and biological activity upon HS and heparin vary from high levels of sequence specificity to a dependence on charge. In contrast to these opposing opinions, we will argue that the evidence supports both a level of redundancy and a degree of selectivity in the structure–activity relationship. The relationship between this apparent redundancy, the multi-dentate nature of heparin and HS polysaccharide chains, their involvement in protein networks and the multiple binding sites on proteins, each possessing different properties, will also be considered. Finally, the role of cations in modulating HS/heparin activity will be reviewed and some of the implications for structure–activity relationships and regulation will be discussed.

scholarly journals Pivotal role of Acitretin nanovesicular gel for effective treatment of psoriasis: ex vivo–in vivo evaluation study

2018 ◽  
Vol Volume 13 ◽  
pp. 1059-1079 ◽  
Author(s):  
Irhan Abu Hashim ◽  
Noha Abo El-Magd ◽  
Ahmed El-Sheakh ◽  
Mohammed Hamed ◽  
Abd El-Gawad Abd El-Gawad
Keyword(s):  
Effective Treatment ◽  
Ex Vivo ◽  
Evaluation Study ◽  
Pivotal Role ◽  
In Vivo Evaluation

scholarly journals The pathophysiologic role of the protein kinase Cδ pathway in the intervertebral discs of rabbits and mice: In vitro, ex vivo, and in vivo studies

2012 ◽  
Vol 64 (6) ◽  
pp. 1950-1959 ◽  
Author(s):  
Michael B. Ellman ◽  
Jae-Sung Kim ◽  
Howard S. An ◽  
Jeffrey S. Kroin ◽  
Xin Li ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Ex Vivo ◽  
Intervertebral Discs ◽  
In Vivo Studies ◽  
Protein Kinase Cδ

Abstract P283: Parkin Mediates Mitophagy in Cardioprotection

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Allen M Andres ◽  
Chengqun Huang ◽  
Eric P Ratliff ◽  
Genaro Hernandez ◽  
Pamela Lee ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Wild Type ◽  
Simulated Ischemia ◽  
Selective Targeting ◽  
Cardioprotective Effects ◽  
Mitochondrial Turnover ◽  
First Time

Autophagy-dependent mitochondrial turnover in response to cellular stress is necessary for maintaining cellular homeostasis. However, the mechanisms that govern the selective targeting of damaged mitochondria are poorly understood. Parkin, an E3 ubiquitin ligase, has been shown to be essential for the selective clearance of damaged mitochondria. Parkin is expressed in the heart, yet its function has not been investigated in the context of cardioprotection. We previously reported that autophagy is required for cardioprotection by ischemic preconditioning (IPC). In the present study, we used simulated ischemia in vitro and IPC in hearts (in vivo and ex vivo) to investigate the role of Parkin in mediating cardioprotection. In HL-1 cells, simulated ischemia induced Parkin translocation to mitochondria and mitochondrial elimination. Mitochondrial loss was blunted in Atg5-deficient cells, revealing the requirement for autophagy in mitochondrial elimination. Consistent with previous reports implicating p62/SQSTM1 in mitophagy, we found that downregulation of p62 attenuated mitophagy and exacerbated cell death in HL-1 cardiomyocytes subjected to simulated ischemia. While wild type mice showed p62 translocation to mitochondria after IPC, Parkin knockout mice exhibited attenuated translocation of p62 to mitochondria. Importantly, ablation of Parkin in mice abolished the cardioprotective effects of IPC. These results reveal for the first time the crucial role of Parkin and mitophagy in cardioprotection.

Abstract WP498: Impaired Pericyte Constriction and Cerebral Blood Flow Autoregulationin Diabetes

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Yedan Liu ◽  
Shaoxun Wang ◽  
Ya Guo ◽  
Huawei Zhang ◽  
Richard Roman ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Ex Vivo ◽  
Mitochondrial Dynamics ◽  
Vascular Cognitive Impairment ◽  
Treated Group ◽  
Diabetic Rats ◽  
Cerebrovascular Function

Diabetes is the primary pathological factor attributed to Alzheimer’s disease and vascular cognitive impairment. Previous studies demonstrated that hyperglycemia promoted oxidative stress in the cerebral vasculature. Cerebrovascular pericytes contribute to maintaining blood-brain barrier (BBB) integrity and regulating cerebral blood flow (CBF). However, whether hyperglycemia diminishes the contractile capability of pericytes, impairs CBF autoregulation and increases BBB permeability are unclear. In the present study, we examined the role of pericytes in cerebrovascular function and cognition in diabetes using cell culture in vitro , isolated penetrating arterioles ex vivo and CBF autoregulation in vivo . Reactive oxygen species were elevated in high glucose (HG, 30 mM) treated vs. normal glucose (NG, 5.5 mM) treated pericytes. Further, mitochondrial superoxide production was increased in HG-treated vs. NG-treated group (13.24 ± 1.01 arbitrary unit (a.u.)/30min vs. 6.98 ± 0.36 a.u./30min). Mitochondrial respiration decreased in HG-treated vs. NG-treated pericytes (3718 ± 185.9 pmol/min/mg, n=10 vs. 4742 ± 284.5 pmol/min/mg, n=10) as measured by a Seahorse XFe24 analyzer. HG-treated pericytes displayed fragmented mitochondria in association with increased fission protein (DRP1) and decreased fusion protein (OPA1) expression. HG-treated pericytes displayed lower contractile capability than NG-treated cells (20.23 ± 7.15% vs. 29.46 ± 9.41%). The myogenic response was impaired in penetrating arterioles isolated from diabetic rats in comparison with non-diabetic rats. Autoregulation of CBF measured by a laser Doppler flowmeter was impaired in diabetic rats compared with non-diabetic rats. Diabetic rats exhibited greater BBB leakage than control rats. The cognitive function was examined using an eight-arm water maze. Diabetic rats took longer time to escape than the non-diabetic rats indicating learning and memory deficits. In conclusion, hyperglycemia induces pericyte dysfunction by altering mitochondrial dynamics and diminishing contractile capability, which promotes BBB leakage, decreases CBF autoregulation and contributes to diabetes-related dementia.

scholarly journals ROLE OF NITRIC OXIDE (NO) IN CAPSAICIN MEDIATED ANTI-PLATELET ACTIVITY IN IN VITRO, IN VIVO, EX-VIVO MODEL OF PLATELET AGGREGATION ASSAY AND ARTERIAL THROMBOSIS IN RAT: POTENTIAL THERAPEUTIC TARGET?

2018 ◽  
Vol 10 (4) ◽  
pp. 44
Author(s):  
Mihir K Patel ◽  
Kiranj K. Chaudagar ◽  
Anita A. Mehta
Keyword(s):  
Platelet Aggregation ◽  
Arterial Thrombosis ◽  
Ex Vivo ◽  
Platelet Activity ◽  
Aggregation Assay ◽  
Thrombosis Model ◽  
Platelet Aggregation Assay

Objective: Although recent advances in the treatment of congestive heart disease, mortality among patients’ remains a questionable remark. Therefore, we evaluated the role of capsaicin on in vitro and ex vivo platelet aggregation induced by Adenosine Di-Phosphate (ADP) as well as in in vivo thrombosis models and role of NO, KATP was also identified in the capsaicin-induced anti-platelet animal model as well as in vivo model of arterial thrombosis.Methods: According to body weight wistar rats were divided into five groups. Group I and Group II was treated with saline and capsaicin (3 mg/kg, i. v), while animals from Group III were treated with N(ω)-nitro-L-arginine methyl ester (L-NAME) (30 mg/kg, i. v) 30 min before administration of capsaicin (3 mg/kg, i. v). Group IV animals were treated with glibenclamide (10 mg/kg,i. v) 30 min before administration of capsaicin (3 mg/kg, i. v). Group V was considered as a positive control and administered clopidogrel (30 mg/kg, p. o). Animals were subjected for in vitro, ex-vivo platelet aggregation assay. ADP (30µM) was utilized as an aggregating agent in these experiments. After these assays; animals of each group were subjected for subaqueous tail bleeding time in a rat model and FeCl3-induced arterial thrombosis model in rats.Results: In ADP-induced in vitro platelet aggregation, a significant reduction in % platelet aggregation was observed at 50µM (64.35±4.641) and 100µM (52.72±4.192) concentration of capsaicin as compared to vehicle control (85.82±3.716). Capsaicin (3 mg/kg, i. v) also showed a significant reduction (49.53±4.075) in ex-vivo ADP-induced platelet aggregation as compared to vehicle control (89.38±2.057). In FeCl3 induced arterial thrombosis model, Capsaicin (3 mg/kg, i. v) exhibited an increase in time to occlusion in this rodent model and presence of the L-NAME and glibenclamide had inhibited the activity of capsaicin.Conclusion: In our study, capsaicin (50 µM, 100µM) exhibited potent anti-platelet activity in ADP-induced platelet aggregation, similarly capsaicin exhibited significant anti-platelet action in the ex-vivo study. Moreover, the presence of L-NAME and glibenclamide inhibited the anti-thrombotic and anti-platelet action of capsaicin. Therefore, it was concluded that NO and KATP may be involved in the anti-thrombotic action of capsaicin.

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