22 results on '"Stanley CP"'
Search Results
2. Sex, Endothelial Cell Functions, and Peripheral Artery Disease.
- Author
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Cartland SP, Stanley CP, Bursill C, Passam F, Figtree GA, Patel S, Loa J, Golledge J, Robinson DA, Aitken SJ, and Kavurma MM
- Subjects
- Male, Humans, Female, Lower Extremity blood supply, Intermittent Claudication, Endothelial Cells, Risk Factors, Peripheral Arterial Disease therapy, Atherosclerosis
- Abstract
Peripheral artery disease (PAD) is caused by blocked arteries due to atherosclerosis and/or thrombosis which reduce blood flow to the lower limbs. It results in major morbidity, including ischemic limb, claudication, and amputation, with patients also suffering a heightened risk of heart attack, stroke, and death. Recent studies suggest women have a higher prevalence of PAD than men, and with worse outcomes after intervention. In addition to a potential unconscious bias faced by women with PAD in the health system, with underdiagnosis, and lower rates of guideline-based therapy, fundamental biological differences between men and women may be important. In this review, we highlight sexual dimorphisms in endothelial cell functions and how they may impact PAD pathophysiology in women. Understanding sex-specific mechanisms in PAD is essential for the development of new therapies and personalized care for patients with PAD.
- Published
- 2023
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3. The Role of Oxidants in Percutaneous Coronary Intervention-Induced Endothelial Dysfunction: Can We Harness Redox Signaling to Improve Clinical Outcomes?
- Author
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Wolhuter K, Kong SMY, Stanley CP, and Kovacic JC
- Subjects
- Humans, Oxidants, Treatment Outcome, Oxidation-Reduction, Percutaneous Coronary Intervention adverse effects, Coronary Artery Disease therapy
- Abstract
Significance: Coronary artery disease (CAD) is commonly treated using percutaneous coronary interventions (PCI). However, PCI with stent placement damages the endothelium, and failure to restore endothelial function may result in PCI failure with poor patient outcomes. Recent Advances: Oxidative signaling is central to maintaining endothelial function. Potentiation of oxidant production, as observed post-PCI, results in endothelial dysfunction (ED). This review delves into our current understanding of the physiological role that endothelial-derived oxidants play within the vasculature and the effects of altered redox signaling during dysfunction. We then examine the impact of PCI and intracoronary stent placement on oxidant production in the endothelium, which can culminate in stent failure. Finally, we explore how recent advances in PCI and stent technologies aim to mitigate PCI-induced oxidative damage and improve clinical outcomes. Critical Issues: Current PCI technologies exacerbate cellular oxidant levels, driving ED. If left uncontrolled, oxidative signaling leads to increased intravascular inflammation, restenosis, and neoatherosclerosis. Future Directions: Through the development of novel biomaterials and therapeutics, we can limit PCI-induced oxidant production, allowing for the restoration of a healthy endothelium and preventing CAD recurrence.
- Published
- 2023
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4. Destabilization of Atherosclerotic Plaque by Bilirubin Deficiency.
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Chen W, Tumanov S, Stanley CP, Kong SMY, Nadel J, Vigder N, Newington DL, Wang XS, Dunn LL, and Stocker R
- Subjects
- Humans, Animals, Mice, Bilirubin, Constriction, Pathologic, Proteomics, Antioxidants, Hemorrhage, Heme, Apolipoproteins E, Lipids, Disease Models, Animal, Plaque, Atherosclerotic pathology, Cardiovascular Diseases, Atherosclerosis metabolism
- Abstract
Background: The rupture of atherosclerotic plaque contributes significantly to cardiovascular disease. Plasma concentrations of bilirubin-a byproduct of heme catabolism-inversely associate with risk of cardiovascular disease, although the link between bilirubin and atherosclerosis remains unclear., Methods: To assess the role of bilirubin in atherosclerotic plaque stability, we crossed Bvra
-/- with Apoe-/- mice and used the tandem stenosis model of plaque instability. Human coronary arteries were obtained from heart transplant recipients. Analysis of bile pigments, heme metabolism, and proteomics were performed by liquid chromatography tandem mass spectrometry. MPO (myeloperoxidase) activity was determined by in vivo molecular magnetic resonance imaging, liquid chromatography tandem mass spectrometry analysis, and immunohistochemical determination of chlorotyrosine. Systemic oxidative stress was evaluated by plasma concentrations of lipid hydroperoxides and the redox status of circulating Prx2 (peroxiredoxin 2), whereas arterial function was assessed by wire myography. Atherosclerosis and arterial remodeling were quantified by morphometry and plaque stability by fibrous cap thickness, lipid accumulation, infiltration of inflammatory cells, and the presence of intraplaque hemorrhage., Results: Compared with Bvra+/+ Apoe-/- tandem stenosis littermates, Bvra-/- Apoe-/- tandem stenosis mice were deficient in bilirubin, showed signs of increased systemic oxidative stress, endothelial dysfunction, as well as hyperlipidemia, and had a higher atherosclerotic plaque burden. Heme metabolism was increased in unstable compared with stable plaque of both Bvra+/+ Apoe-/- and Bvra-/- Apoe-/- tandem stenosis mice and in human coronary plaques. In mice, Bvra deletion selectively destabilized unstable plaque, characterized by positive arterial remodeling and increased cap thinning, intraplaque hemorrhage, infiltration of neutrophils, and MPO activity. Proteomic analysis confirmed Bvra deletion enhanced extracellular matrix degradation, recruitment and activation of neutrophils, and associated oxidative stress in unstable plaque., Conclusions: Bilirubin deficiency, resulting from global Bvra deletion, generates a proatherogenic phenotype and selectively enhances neutrophil-mediated inflammation and destabilization of unstable plaque, thereby providing a link between bilirubin and cardiovascular disease risk.- Published
- 2023
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5. Endothelial cell dysfunction: Implications for the pathogenesis of peripheral artery disease.
- Author
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Kavurma MM, Bursill C, Stanley CP, Passam F, Cartland SP, Patel S, Loa J, Figtree GA, Golledge J, Aitken S, and Robinson DA
- Abstract
Peripheral artery disease (PAD) is caused by occluded or narrowed arteries that reduce blood flow to the lower limbs. The treatment focuses on lifestyle changes, management of modifiable risk factors and vascular surgery. In this review we focus on how Endothelial Cell (EC) dysfunction contributes to PAD pathophysiology and describe the largely untapped potential of correcting endothelial dysfunction. Moreover, we describe current treatments and clinical trials which improve EC dysfunction and offer insights into where future research efforts could be made. Endothelial dysfunction could represent a target for PAD therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kavurma, Bursill, Stanley, Passam, Cartland, Patel, Loa, Figtree, Golledge, Aitken and Robinson.)
- Published
- 2022
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6. Human coronary microvascular contractile dysfunction associates with viable synthetic smooth muscle cells.
- Author
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Dora KA, Borysova L, Ye X, Powell C, Beleznai TZ, Stanley CP, Bruno VD, Starborg T, Johnson E, Pielach A, Taggart M, Smart N, and Ascione R
- Subjects
- Animals, Coronary Vessels pathology, Humans, Muscle Contraction, Myocytes, Smooth Muscle metabolism, Swine, Heart Valve Diseases metabolism, Muscle, Smooth, Vascular metabolism
- Abstract
Aims: Coronary microvascular smooth muscle cells (SMCs) respond to luminal pressure by developing myogenic tone (MT), a process integral to the regulation of microvascular perfusion. The cellular mechanisms underlying poor myogenic reactivity in patients with heart valve disease are unknown and form the focus of this study., Methods and Results: Intramyocardial coronary micro-arteries (IMCAs) isolated from human and pig right atrial (RA) appendage and left ventricular (LV) biopsies were studied using pressure myography combined with confocal microscopy. All RA- and LV-IMCAs from organ donors and pigs developed circa 25% MT. In contrast, 44% of human RA-IMCAs from 88 patients with heart valve disease had poor (<10%) MT yet retained cell viability and an ability to raise cytoplasmic Ca2+ in response to vasoconstrictor agents. Comparing across human heart chambers and species, we found that based on patient medical history and six tests, the strongest predictor of poor MT in IMCAs was increased expression of the synthetic marker caldesmon relative to the contractile marker SM-myosin heavy chain. In addition, high resolution imaging revealed a distinct layer of longitudinally aligned SMCs between ECs and radial SMCs, and we show poor MT was associated with disruptions in these cellular alignments., Conclusion: These data demonstrate the first use of atrial and ventricular biopsies from patients and pigs to reveal that impaired coronary MT reflects a switch of viable SMCs towards a synthetic phenotype, rather than a loss of SMC viability. These arteries represent a model for further studies of coronary microvascular contractile dysfunction., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)
- Published
- 2022
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7. Ankle conFUSION: The quality and readability of information on the internet relating to ankle arthrodesis.
- Author
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Irwin SC, Lennon DT, Stanley CP, Sheridan GA, and Walsh JC
- Subjects
- Ankle, Arthrodesis, Humans, Internet, United States, Comprehension, Health Literacy
- Abstract
Background: The internet is an important source of information for patients undergoing surgery. Multiple studies have identified inappropriately high reading levels of patient information online. The average reading level in the United States is 7-8th grade. Multiple organisations have recommended that patient information not exceed 6th grade level. This study aims to evaluate the reading levels and quality of information regarding ankle fusion surgery online., Methods: Google, Bing and Yahoo were searched (MeSH "ankle fusion", "ankle arthrodesis") and the top 30 URLs analysed. Readability was assessed using an online readability calculator to produce 3 scores (Gunning FOG, Flesch Kincaid Grade and Flesch Reading Ease). Quality was assessed using a HONcode detection web-extension and the JAMA benchmark criteria., Results: Ninety-eight webpages were identified. The mean Flesch Kincaid Grade level was 9.24 ± 2.33 (95% CI 8.78-9.71). The mean Gunning FOG grade was 10.88 ± 3.1 (95% CI 10.26-11.5). The mean Flesch Reading Ease score was 49.88 ± 14.46 (95% CI 46.98-52.78). 7 webpages were at or below the 6th grade reading level. The mean JAMA score was 1.34 ± 1.32 out of 4 (95% CI 1.07-1.6). 14 websites were HONcode accredited., Conclusion: The overall readability of medical information online is too high for the average patient. Given the important role that health literacy provides in patient reported outcomes, improving the readability and quality of these materials is imperative. Awareness by the general public is essential for them to critically appraise the information they receive online., Competing Interests: Declaration of competing interest None declared., (Copyright © 2020 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2021
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8. Hydrogen peroxide signaling via its transformation to a stereospecific alkyl hydroperoxide that escapes reductive inactivation.
- Author
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Queiroz RF, Stanley CP, Wolhuter K, Kong SMY, Rajivan R, McKinnon N, Nguyen GTH, Roveri A, Guttzeit S, Eaton P, Donald WA, Ursini F, Winterbourn CC, Ayer A, and Stocker R
- Subjects
- Animals, Cyclic GMP-Dependent Protein Kinase Type I, Endothelial Cells metabolism, Homeodomain Proteins metabolism, Indoleamine-Pyrrole 2,3,-Dioxygenase metabolism, Inflammation, Male, Mice, Mice, Inbred C57BL, Oxidation-Reduction, Peroxidases genetics, Peroxiredoxins metabolism, Tryptophan metabolism, Hydrogen Peroxide metabolism, Peroxidases chemistry, Peroxidases metabolism, Signal Transduction
- Abstract
During systemic inflammation, indoleamine 2,3-dioxygenase 1 (IDO1) becomes expressed in endothelial cells where it uses hydrogen peroxide (H
2 O2 ) to oxidize L-tryptophan to the tricyclic hydroperoxide, cis-WOOH, that then relaxes arteries via oxidation of protein kinase G 1α. Here we show that arterial glutathione peroxidases and peroxiredoxins that rapidly eliminate H2 O2 , have little impact on relaxation of IDO1-expressing arteries, and that purified IDO1 forms cis-WOOH in the presence of peroxiredoxin 2. cis-WOOH oxidizes protein thiols in a selective and stereospecific manner. Compared with its epimer trans-WOOH and H2 O2 , cis-WOOH reacts slower with the major arterial forms of glutathione peroxidases and peroxiredoxins while it reacts more readily with its target, protein kinase G 1α. Our results indicate a paradigm of redox signaling by H2 O2 via its enzymatic conversion to an amino acid-derived hydroperoxide that 'escapes' effective reductive inactivation to engage in selective oxidative activation of key target proteins., (© 2021. The Author(s).)- Published
- 2021
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9. Regulation of vascular tone and blood pressure by singlet molecular oxygen in inflammation.
- Author
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Stanley CP and Stocker R
- Subjects
- Blood Pressure, Humans, Inflammation, Oxygen, Indoleamine-Pyrrole 2,3,-Dioxygenase, Singlet Oxygen
- Abstract
Purpose of Review: The principle aim of this review is to prompt vascular researchers interested in vascular inflammation and oxidative stress to consider singlet molecular oxygen (1O2) as a potentially relevant contributor. A secondary goal is to propose novel treatment strategies to address haemodynamic complications associated with septic shock., Recent Findings: Increased inflammation and oxidative stress are hallmarks of a range of vascular diseases. We recently showed that in systemic inflammation and oxidative stress associated with models of inflammation including sepsis, the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase-1 (Ido1) contributes to hypotension and decreased blood pressure through production of singlet molecular oxygen (1O2). Once formed, 1O2 converts tryptophan bound to Ido1 to a vasoactive hydroperoxide which decreases arterial tone and blood pressure via oxidation of a specific cysteine residue of protein kinase G1α., Summary: These works show, for the first time, that 1O2 contributes to arterial redox signalling and that Ido1 contributes to the regulation of blood pressure through production of a novel tryptophan-derived hydroperoxide, thus presenting a new signalling pathway as novel target in the treatment of blood pressure disorders such as sepsis., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2021
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10. Inhibition of MPO (Myeloperoxidase) Attenuates Endothelial Dysfunction in Mouse Models of Vascular Inflammation and Atherosclerosis.
- Author
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Cheng D, Talib J, Stanley CP, Rashid I, Michaëlsson E, Lindstedt EL, Croft KD, Kettle AJ, Maghzal GJ, and Stocker R
- Subjects
- Animals, Apolipoproteins E physiology, Atherosclerosis physiopathology, Disease Models, Animal, Endothelial Cells physiology, Enzyme Inhibitors pharmacology, Inflammation physiopathology, Male, Mice, Mice, Inbred C57BL, Peroxidase physiology, Vascular Diseases physiopathology, Atherosclerosis drug therapy, Endothelial Cells drug effects, Inflammation drug therapy, Peroxidase antagonists & inhibitors, Vascular Diseases drug therapy
- Abstract
Objective- Inflammation-driven endothelial dysfunction initiates and contributes to the progression of atherosclerosis, and MPO (myeloperoxidase) has been implicated as a potential culprit. On release by circulating phagocytes, MPO is thought to contribute to endothelial dysfunction by limiting NO bioavailability via formation of reactive oxidants including hypochlorous acid. However, it remains largely untested whether specific pharmacological inhibition of MPO attenuates endothelial dysfunction. We, therefore, tested the ability of a mechanism-based MPO inhibitor, AZM198, to inhibit endothelial dysfunction in models of vascular inflammation. Approach and Results- Three models of inflammation were used: femoral cuff, the tandem stenosis model of plaque rupture in Apoe
-/- mice, and C57BL/6J mice fed a high-fat, high-carbohydrate diet as a model of insulin resistance. Endothelial dysfunction was observed in all 3 models, and oral administration of AZM198 significantly improved endothelial function in the femoral cuff and tandem stenosis models only. Improvement in endothelial function was associated with decreased arterial MPO activity, determined by the in vivo conversion of hydroethidine to 2-chloroethidium, without affecting circulating inflammatory cytokines or arterial MPO content. Mechanistic studies in Mpo-/- mice confirmed the contribution of MPO to endothelial dysfunction and revealed oxidation of sGC (soluble guanylyl cyclase) as the underlying cause of the observed limited NO bioavailability. Conclusions- Pharmacological inhibition of MPO is a potential strategy to limit endothelial dysfunction in vascular inflammation. Visual Overview- An online visual overview is available for this article.- Published
- 2019
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11. Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation.
- Author
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Stanley CP, Maghzal GJ, Ayer A, Talib J, Giltrap AM, Shengule S, Wolhuter K, Wang Y, Chadha P, Suarna C, Prysyazhna O, Scotcher J, Dunn LL, Prado FM, Nguyen N, Odiba JO, Baell JB, Stasch JP, Yamamoto Y, Di Mascio P, Eaton P, Payne RJ, and Stocker R
- Subjects
- Animals, Cell Line, Cyclic GMP-Dependent Protein Kinase Type I antagonists & inhibitors, Cyclic GMP-Dependent Protein Kinase Type I chemistry, Cyclic GMP-Dependent Protein Kinase Type I metabolism, Cysteine metabolism, Enzyme Activation drug effects, Female, Humans, Hydrogen Peroxide chemistry, Hydrogen Peroxide metabolism, Hydrogen Peroxide pharmacology, Indoleamine-Pyrrole 2,3,-Dioxygenase chemistry, Indoleamine-Pyrrole 2,3,-Dioxygenase metabolism, Inflammation enzymology, Male, Oxidation-Reduction drug effects, Rats, Signal Transduction, Singlet Oxygen chemistry, Tryptophan chemistry, Tryptophan metabolism, Blood Pressure physiology, Inflammation blood, Inflammation physiopathology, Singlet Oxygen metabolism, Vasodilator Agents metabolism
- Abstract
Singlet molecular oxygen (
1 O2 ) has well-established roles in photosynthetic plants, bacteria and fungi1-3 , but not in mammals. Chemically generated1 O2 oxidizes the amino acid tryptophan to precursors of a key metabolite called N-formylkynurenine4 , whereas enzymatic oxidation of tryptophan to N-formylkynurenine is catalysed by a family of dioxygenases, including indoleamine 2,3-dioxygenase 15 . Under inflammatory conditions, this haem-containing enzyme is expressed in arterial endothelial cells, where it contributes to the regulation of blood pressure6 . However, whether indoleamine 2,3-dioxygenase 1 forms1 O2 and whether this contributes to blood pressure control have remained unknown. Here we show that arterial indoleamine 2,3-dioxygenase 1 regulates blood pressure via formation of1 O2 . We observed that in the presence of hydrogen peroxide, the enzyme generates1 O2 and that this is associated with the stereoselective oxidation of L-tryptophan to a tricyclic hydroperoxide via a previously unrecognized oxidative activation of the dioxygenase activity. The tryptophan-derived hydroperoxide acts in vivo as a signalling molecule, inducing arterial relaxation and decreasing blood pressure; this activity is dependent on Cys42 of protein kinase G1α. Our findings demonstrate a pathophysiological role for1 O2 in mammals through formation of an amino acid-derived hydroperoxide that regulates vascular tone and blood pressure under inflammatory conditions.- Published
- 2019
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12. Endothelial indoleamine 2,3-dioxygenase-1 regulates the placental vascular tone and is deficient in intrauterine growth restriction and pre-eclampsia.
- Author
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Zardoya-Laguardia P, Blaschitz A, Hirschmugl B, Lang I, Herzog SA, Nikitina L, Gauster M, Häusler M, Cervar-Zivkovic M, Karpf E, Maghzal GJ, Stanley CP, Stocker R, Wadsack C, Frank S, and Sedlmayr P
- Subjects
- Adult, Arteries physiopathology, Endothelium, Vascular metabolism, Female, Fetal Growth Retardation pathology, Fetal Growth Retardation physiopathology, Gene Expression Regulation, Enzymologic, Humans, Pre-Eclampsia pathology, Pre-Eclampsia physiopathology, Pregnancy, Vasodilation, Blood Vessels physiopathology, Endothelium, Vascular enzymology, Fetal Growth Retardation enzymology, Placenta blood supply, Pre-Eclampsia enzymology
- Abstract
Indoleamine 2,3-dioxygenase-1 (IDO1) mediates the degradation of L-tryptophan (L-Trp) and is constitutively expressed in the chorionic vascular endothelium of the human placenta with highest levels in the microvasculature. Given that endothelial expression of IDO1 has been shown to regulate vascular tone and blood pressure in mice under the condition of systemic inflammation, we asked whether IDO1 is also involved in the regulation of placental blood flow and if yes, whether this function is potentially impaired in intrauterine growth restriction (IUGR) and pre-eclampsia (PE). In the large arteries of the chorionic plate L-Trp induced relaxation only after upregulation of IDO1 using interferon gamma and tumor necrosis factor alpha. However, ex vivo placental perfusion of pre-constricted cotyledonic vasculature with L-Trp decreases the vessel back pressure without prior IDO1 induction. Further to this finding, IDO1 protein expression and activity is reduced in IUGR and PE when compared to gestational age-matched control tissue. These data suggest that L-Trp catabolism plays a role in the regulation of placental vascular tone, a finding which is potentially linked to placental and fetal growth. In this context our data suggest that IDO1 deficiency is related to the pathogenesis of IUGR and PE.
- Published
- 2018
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13. The endocannabinoid anandamide causes endothelium-dependent vasorelaxation in human mesenteric arteries.
- Author
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Stanley CP, Hind WH, Tufarelli C, and O'Sullivan SE
- Subjects
- Adult, Aged, Aged, 80 and over, Aorta drug effects, Cannabinoids pharmacology, Cyclohexanols, Endothelial Cells drug effects, Endothelium, Vascular metabolism, Female, Humans, Intracellular Signaling Peptides and Proteins, Male, Mesenteric Arteries metabolism, Middle Aged, Nitric Oxide metabolism, RNA, Messenger metabolism, Receptor, Cannabinoid, CB1 metabolism, Receptor, Cannabinoid, CB2 metabolism, Arachidonic Acids pharmacology, Endocannabinoids pharmacology, Mesenteric Arteries drug effects, Polyunsaturated Alkamides pharmacology, Vasodilation drug effects
- Abstract
The endocannabinoid anandamide (AEA) causes vasorelaxation in animal studies. Although circulating AEA levels are increased in many pathologies, little is known about its vascular effects in humans. The aim of this work was to characterise the effects of AEA in human arteries. Ethical approval was granted to obtain mesenteric arteries from patients (n=31) undergoing bowel resection. Wire myography was used to probe the effects and mechanisms of action of AEA. RT-PCR was used to confirm the presence of receptor mRNA in human aortic endothelial cells (HAECs) and intracellular signalling proteins were measured using multiplex technology. AEA caused vasorelaxation of precontracted human mesenteric arteries with an R
max of ∼30%. A synthetic CB1 agonist (CP55940) caused greater vasorelaxation (Rmax ∼60%) while a CB2 receptor agonist (HU308) had no effect on vascular tone. AEA-induced vasorelaxation was inhibited by removing the endothelium, inhibition of nitric oxide (NO) synthase, antagonising the CB1 receptor and antagonising the proposed novel endothelial cannabinoid receptor (CBe ). AEA-induced vasorelaxation was not affected by CB2 antagonism, by depleting sensory neurotransmitters, or inhibiting cyclooxygenase activity. RT-PCR showed CB1 but not CB2 receptors were present in HAECs, and AEA and CP55940 had similar profiles in HAECs (increased phosphorylation of JNK, NFκB, ERK, Akt, p70s6K, STAT3 and STAT5). Post hoc analysis of the data set showed that overweight patients and those taking paracetamol had reduced vasorelaxant responses to AEA. These data show that AEA causes moderate endothelium-dependent, NO-dependent vasorelaxation in human mesenteric arteries via activation of CB1 receptors., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2016
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14. Isolated Human Pulmonary Artery Structure and Function Pre- and Post-Cardiopulmonary Bypass Surgery.
- Author
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Dora KA, Stanley CP, Al Jaaly E, Fiorentino F, Ascione R, Reeves BC, and Angelini GD
- Subjects
- Adult, Aged, Aged, 80 and over, Biopsy, Coronary Artery Disease pathology, Coronary Artery Disease physiopathology, Dose-Response Relationship, Drug, Elective Surgical Procedures, Female, Humans, Male, Microscopy, Confocal, Middle Aged, Muscle, Smooth, Vascular drug effects, Muscle, Smooth, Vascular pathology, Muscle, Smooth, Vascular physiopathology, Pulmonary Artery drug effects, Pulmonary Artery pathology, Pulmonary Artery physiopathology, Randomized Controlled Trials as Topic, Treatment Outcome, Vasoconstriction drug effects, Vasoconstrictor Agents pharmacology, Vasodilation drug effects, Vasodilator Agents pharmacology, Cardiopulmonary Bypass adverse effects, Coronary Artery Bypass adverse effects, Coronary Artery Disease surgery, Muscle, Smooth, Vascular surgery, Pulmonary Artery surgery
- Abstract
Background: Pulmonary dysfunction is a known complication after cardiac surgery using cardiopulmonary bypass, ranging from subclinical functional changes to prolonged postoperative ventilation, acute lung injury, and acute respiratory distress syndrome. Whether human pulmonary arterial function is compromised is unknown. The aim of the present study was to compare the structure and function of isolated and cannulated human pulmonary arteries obtained from lung biopsies after the chest was opened (pre-cardiopulmonary bypass) to those obtained at the end of cardiopulmonary bypass (post-cardiopulmonary bypass) from patients undergoing coronary artery bypass graft surgery., Methods and Results: Pre- and post-cardiopulmonary bypass lung biopsies were received from 12 patients undergoing elective surgery. Intralobular small arteries were dissected, cannulated, pressurized, and imaged using confocal microscopy. Functionally, the thromboxane mimetic U46619 produced concentration-dependent vasoconstriction in 100% and 75% of pre- and post-cardiopulmonary bypass arteries, respectively. The endothelium-dependent agonist bradykinin stimulated vasodilation in 45% and 33% of arteries pre- and post-cardiopulmonary bypass, respectively. Structurally, in most arteries smooth muscle cells aligned circumferentially; live cell viability revealed that although 100% of smooth muscle and 90% of endothelial cells from pre-cardiopulmonary bypass biopsies had intact membranes and were considered viable, only 60% and 58%, respectively, were viable from post-cardiopulmonary bypass biopsies., Conclusions: We successfully investigated isolated pulmonary artery structure and function in fresh lung biopsies from patients undergoing heart surgery. Pulmonary artery contractile tone and endothelium-dependent dilation were significantly reduced in post-cardiopulmonary bypass biopsies. The decreased functional responses were associated with reduced cell viability., Clinical Trial Registration: URL: http://www.isrctn.com/ISRCTN34428459. Unique identifier: ISRCTN 34428459., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)
- Published
- 2016
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15. Cannabidiol causes endothelium-dependent vasorelaxation of human mesenteric arteries via CB1 activation.
- Author
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Stanley CP, Hind WH, Tufarelli C, and O'Sullivan SE
- Subjects
- Adult, Aged, Aged, 80 and over, Endothelium, Vascular metabolism, Female, Humans, Male, Middle Aged, Multiple Sclerosis drug therapy, Nitric Oxide metabolism, Vasodilator Agents pharmacology, Cannabidiol pharmacology, Endothelium, Vascular drug effects, Mesenteric Arteries drug effects, Receptor, Cannabinoid, CB1 metabolism, Vasodilation drug effects
- Abstract
Aims: The protective effects of cannabidiol (CBD) have been widely shown in preclinical models and have translated into medicines for the treatment of multiple sclerosis and epilepsy. However, the direct vascular effects of CBD in humans are unknown., Methods and Results: Using wire myography, the vascular effects of CBD were assessed in human mesenteric arteries, and the mechanisms of action probed pharmacologically. CBD-induced intracellular signalling was characterized using human aortic endothelial cells (HAECs). CBD caused acute, non-recoverable vasorelaxation of human mesenteric arteries with an Rmax of ∼ 40%. This was inhibited by cannabinoid receptor 1 (CB1) receptor antagonists, desensitization of transient receptor potential channels using capsaicin, removal of the endothelium, and inhibition of potassium efflux. There was no role for cannabinoid receptor-2 (CB2) receptor, peroxisome proliferator activated receptor (PPAR)γ, the novel endothelial cannabinoid receptor (CBe), or cyclooxygenase. CBD-induced vasorelaxation was blunted in males, and in patients with type 2 diabetes or hypercholesterolemia. In HAECs, CBD significantly reduced phosphorylated JNK, NFκB, p70s6 K and STAT5, and significantly increased phosphorylated CREB, ERK1/2, and Akt levels. CBD also increased phosphorylated eNOS (ser1177), which was correlated with increased levels of ERK1/2 and Akt levels. CB1 receptor antagonism prevented the increase in eNOS phosphorylation., Conclusion: This study shows, for the first time, that CBD causes vasorelaxation of human mesenteric arteries via activation of CB1 and TRP channels, and is endothelium- and nitric oxide-dependent., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.)
- Published
- 2015
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16. Cyclooxygenase metabolism mediates vasorelaxation to 2-arachidonoylglycerol (2-AG) in human mesenteric arteries.
- Author
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Stanley CP and O'Sullivan SE
- Subjects
- Cyclooxygenase Inhibitors pharmacology, Flurbiprofen pharmacology, Humans, In Vitro Techniques, Indomethacin pharmacology, Mesenteric Arteries physiology, Vasodilation physiology, Arachidonic Acids pharmacology, Cyclooxygenase 1 physiology, Endocannabinoids pharmacology, Glycerides pharmacology, Mesenteric Arteries drug effects, Vasodilation drug effects
- Abstract
Objective: The vasorelaxant effect of 2-arachidonoylglycerol (2-AG) has been well characterised in animals. 2-AG is present in human vascular cells and is up-regulated in cardiovascular pathophysiology. However, the acute vascular actions of 2-AG have not been explored in humans., Approach: Mesenteric arteries were obtained from patients receiving colorectal surgery and mounted on a myograph. Arteries were contracted and 2-AG concentration-response curves were carried out. Mechanisms of action were characterised pharmacologically. Post hoc analysis was carried out to assess the effects of cardiovascular disease/risk factors on 2-AG responses., Results: 2-AG caused vasorelaxation of human mesenteric arteries, independent of cannabinoid receptor or transient receptor potential vanilloid-1 activation, the endothelium, nitric oxide or metabolism via monoacyglycerol lipase or fatty acid amide hydrolase. 2-AG-induced vasorelaxation was reduced in the presence of indomethacin and flurbiprofen, suggesting a role for cyclooxygenase metabolism 2-AG. Responses to 2-AG were also reduced in the presence of Cay10441, L-161982 and potentiated in the presence of AH6809, suggesting that metabolism of 2-AG produces both vasorelaxant and vasoconstrictor prostanoids. Finally, 2-AG-induced vasorelaxation was dependent on potassium efflux and the presence of extracellular calcium., Conclusions: We have shown for the first time that 2-AG causes vasorelaxation of human mesenteric arteries. Vasorelaxation is dependent on COX metabolism, activation of prostanoid receptors (EP4 & IP) and ion channel modulation. 2-AG responses are blunted in patients with cardiovascular risk factors., (Copyright © 2014. Published by Elsevier Ltd.)
- Published
- 2014
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17. Cannabinoids alter endothelial function in the Zucker rat model of type 2 diabetes.
- Author
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Stanley CP, Wheal AJ, Randall MD, and O'Sullivan SE
- Subjects
- Animals, Aorta, Thoracic drug effects, Aorta, Thoracic physiology, Disease Models, Animal, Endothelium, Vascular physiopathology, Femoral Artery drug effects, Femoral Artery physiology, Male, Mesenteric Arteries drug effects, Mesenteric Arteries physiology, Rats, Rats, Zucker, Vasodilation drug effects, Arachidonic Acids pharmacology, Cannabidiol pharmacology, Diabetes Mellitus, Type 2 physiopathology, Endocannabinoids pharmacology, Endothelium, Vascular drug effects, Polyunsaturated Alkamides pharmacology
- Abstract
Circulating levels of anandamide are increased in diabetes, and cannabidiol ameliorates a number of pathologies associated with diabetes. The aim of the present study was to examine how exposure to anandamide or cannabidiol might affect endothelial dysfunction associated with Zucker Diabetic Fatty rats. Age-matched Zucker Diabetic Fatty and Zucker lean rats were killed by cervical dislocation and their arteries mounted on a myograph at 37 °C. Arteries were incubated for 2h with anandamide, cannabidiol or vehicle, contracted, and cumulative concentration-response curves to acetylcholine were constructed. Anandamide (10 µM, 2h) significantly improved the vasorelaxant responses to acetylcholine in aortae and femoral arteries from Zucker Diabetic Fatty rats but not Zucker lean rats. By contrast, anandamide (1 µM, 2h) significantly blunted acetylcholine-induced vasorelaxation in third-order mesenteric arteries (G3) from Zucker Diabetic Fatty rats. Cannabidiol incubation (10 µM, 2h) improved acetylcholine responses in the arteries of Zucker Diabetic Fatty rats (aorta and femoral) and Zucker lean (aorta, femoral and G3 mesenteric), and this effect was greater in the Zucker Diabetic Fatty rat. These studies suggest that increased circulating endocannabinoids may alter vascular function both positively and negatively in type 2 diabetes, and that part of the beneficial effect of cannabidiol in diabetes may be due to improved endothelium-dependent vasorelaxation., (© 2013 Elsevier B.V. All rights reserved.)
- Published
- 2013
- Full Text
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18. Is the cardiovascular system a therapeutic target for cannabidiol?
- Author
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Stanley CP, Hind WH, and O'Sullivan SE
- Subjects
- Animals, Antioxidants pharmacology, Disease Models, Animal, Humans, Anti-Inflammatory Agents pharmacology, Cannabidiol pharmacology, Cardiovascular Diseases drug therapy, Cardiovascular System drug effects
- Abstract
Cannabidiol (CBD) has beneficial effects in disorders as wide ranging as diabetes, Huntington's disease, cancer and colitis. Accumulating evidence now also suggests that CBD is beneficial in the cardiovascular system. CBD has direct actions on isolated arteries, causing both acute and time-dependent vasorelaxation. In vitro incubation with CBD enhances the vasorelaxant responses in animal models of impaired endothelium-dependent vasorelaxation. CBD protects against the vascular damage caused by a high glucose environment, inflammation or the induction of type 2 diabetes in animal models and reduces the vascular hyperpermeability associated with such environments. A common theme throughout these studies is the anti-inflammatory and anti-oxidant effect of CBD. In the heart, in vivo CBD treatment protects against ischaemia-reperfusion damage and against cardiomyopathy associated with diabetes. Similarly, in a different model of ischaemia-reperfusion, CBD has been shown to reduce infarct size and increase blood flow in animal models of stroke, sensitive to 5HT(1A) receptor antagonism. Although acute or chronic CBD treatment seems to have little effect on haemodynamics, CBD reduces the cardiovascular response to models of stress, applied either systemically or intracranially, inhibited by a 5HT(1A) receptor antagonist. In blood, CBD influences the survival and death of white blood cells, white blood cell migration and platelet aggregation. Taken together, these preclinical data appear to support a positive role for CBD treatment in the heart, and in peripheral and cerebral vasculature. However, further work is required to strengthen this hypothesis, establish mechanisms of action and whether similar responses to CBD would be observed in humans., (© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.)
- Published
- 2013
- Full Text
- View/download PDF
19. Developmental transitions in electrical activation patterns in chick embryonic heart.
- Author
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Sedmera D, Reckova M, Bigelow MR, Dealmeida A, Stanley CP, Mikawa T, Gourdie RG, and Thompson RP
- Subjects
- Animals, Electric Stimulation, Electrophysiology, Ventricular Function, Action Potentials, Bundle of His embryology, Chick Embryo physiology, Heart Conduction System embryology, Heart Conduction System physiology, Heart Ventricles embryology
- Abstract
The specialized conduction tissue network mediates coordinated propagation of electrical activity through the adult vertebrate heart. Following activation of the atria, the activation wave is slowed down in the atrioventricular canal or node, then spreads rapidly into the left and right ventricles via the His-Purkinje system (HPS). This results in the ventricle being activated from the apex toward the base and is thought to represent HPS function. The development of mature HPS function in embryogenesis follows significant phases of cardiac morphogenesis. Initially, cardiac impulse propagates in a slow, linear, and isotropic fashion from the sinus venosus at the most caudal portion of the tubular heart. Although the speed of impulse propagation gradually increases, ventricular activation in the looped heart still follows the direction of blood flow. Eventually, the immature base-to-apex sequence of ventricular activation undergoes an apparent reversal, maturing to apex-to-base pattern. The embryonic chick heart has been studied intensively by both electrophysiological and morphological techniques, and the morphology of its conduction system (which is similar to mammals) is well characterized. One interesting but seldom studied feature is the anterior septal branch (ASB), which came sharply to focus (together with the rest of the ventricular conduction system) in our birthdating studies. Using an optical mapping approach, we show that ASB serves to activate ventricular surface between stages 16 and 25, predating the functionality of the His bundle/bundle branches. Heart morphogenesis and conduction system formation are thus linked, and studying the abnormal activation patterns could further our understanding of pathogenesis of congenital heart disease., (copyright 2004 Wiley-Liss, Inc.)
- Published
- 2004
- Full Text
- View/download PDF
20. Hemodynamics is a key epigenetic factor in development of the cardiac conduction system.
- Author
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Reckova M, Rosengarten C, deAlmeida A, Stanley CP, Wessels A, Gourdie RG, Thompson RP, and Sedmera D
- Subjects
- Animals, Chick Embryo, Heart Conduction System embryology, Heart Conduction System physiopathology, Heart Ventricles embryology, Heart Ventricles physiopathology, Hemodynamics, Hypoplastic Left Heart Syndrome embryology, Hypoplastic Left Heart Syndrome metabolism, Hypoplastic Left Heart Syndrome physiopathology, Immunohistochemistry, Myocardium chemistry, Neural Cell Adhesion Molecule L1 analysis, Purkinje Fibers embryology, Purkinje Fibers physiopathology, Sialic Acids analysis, Ventricular Function, Heart Conduction System physiology, Purkinje Fibers physiology
- Abstract
The His-Purkinje system (HPS) is a network of conduction cells responsible for coordinating the contraction of the ventricles. Earlier studies using bipolar electrodes indicated that the functional maturation of the HPS in the chick embryo is marked by a topological shift in the sequence of activation of the ventricle. Namely, at around the completion of septation, an immature base-to-apex sequence of ventricular activation was reported to convert to the apex-to-base pattern characteristic of the mature heart. Previously, we have proposed that hemodynamics and/or mechanical conditioning may be key epigenetic factors in development of the HPS. We thus hypothesized that the timing of the topological shift marking maturation of the conduction system is sensitive to variation in hemodynamic load. Spatiotemporal patterns of ventricular activation (as revealed by high-speed imaging of fluorescent voltage-sensitive dye) were mapped in chick hearts over normal development, and following procedures previously characterized as causing increased (conotruncal banding, CTB) or reduced (left atrial ligation, LAL) hemodynamic loading of the embryonic heart. The results revealed that the timing of the shift to mature activation displays striking plasticity. CTB led to precocious emergence of mature HPS function relative to controls whereas LAL was associated with delayed conversion to apical initiation. The results from our study indicate a critical role for biophysical factors in differentiation of specialized cardiac tissues and provide the basis of a new model for studies of the molecular mechanisms involved in induction and patterning of the HPS in vivo.
- Published
- 2003
- Full Text
- View/download PDF
21. The oldest, toughest cells in the heart.
- Author
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Thompson RP, Reckova M, deAlmeida A, Bigelow MR, Stanley CP, Spruill JB, Trusk TT, and Sedmera D
- Subjects
- Animals, Calcium metabolism, Cell Differentiation physiology, Heart growth & development, Heart Conduction System anatomy & histology, Heart Rate physiology, Humans, Muscle Contraction physiology, Myocardium cytology, Myocardium metabolism, Myocytes, Cardiac cytology, Myocytes, Cardiac metabolism, Aging physiology, Heart anatomy & histology, Heart Conduction System growth & development
- Abstract
We review here the evolution and development of the earliest components of the cardiac pacemaking and conduction system (PCS) and the turnover or persistence of such cells into old age in the adult vertebrate heart. Heart rate is paced by upstream foci of cardiac muscle near the future sinoatrial junction even before contraction begins. As the tubular heart loops, directional blood flow is maintained through coordinated sphincter function in the forming atrioventricular (AV) canal and outflow segments. Propagation of initially peristaltoid contraction along and between these segments appears to be influenced by physical conditioning and orientation of inner muscle layers as well as by their slow relaxation; all characteristic of definitive conduction tissue. As classical elements of the mature conduction system emerge, such inner 'contour fibres' maintain muscular and electrical continuity between atrial and ventricular compartments. Elements of such primordial architecture are visible also in histological and optical electrical study of fish and frog hearts. In the maturing chick heart, cells within core conducting tissues retain early thymidine labels from the tubular heart stage into adult life, dividing only slowly, if at all. Preliminary evidence from mammals suggest similar function and kinetics for these 'oldest, toughest' cells in the hearts of all vertebrates.
- Published
- 2003
22. Pulmonary balloon valvoplasty in late adult life.
- Author
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Gibbs JL, Stanley CP, and Dickinson DF
- Subjects
- Aortic Valve Stenosis congenital, Cardiac Catheterization methods, Female, Hemodynamics, Humans, Middle Aged, Angioplasty, Balloon methods, Aortic Valve Stenosis therapy
- Abstract
A case of severe valvar pulmonary stenosis in a 60-year-old woman is described. Percutaneous balloon valvoplasty was performed without complication and reduced the right ventricular outflow pressure gradient from 95 mm Hg to 25 mm Hg. Balloon valvoplasty is an effective alternative to surgical valvotomy in adults as well as children.
- Published
- 1986
- Full Text
- View/download PDF
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