Search
Showing 741–760 of 2058 publications.
-
Maiocchi, Sophie L.; Alwis, Imala D.; Wu, Mike C.L.; Yuan, Yuping; Jackson, Shaun P.Ischemia-reperfusion (IR) injury is a common complication of a variety of cardiovascular diseases, including ischemic stroke and myocardial infarction (MI). While timely re-establishment of blood flow in a thrombosed artery is the primary goal of acute therapy in these diseases, paradoxically, reperfusion of ischemic tissue can cause widespread microvascular dysfunction that significantly exacerbates organ damage. Reperfusion injury is associated with activation of the humoral and cellular components of the hemostatic and innate immune systems and also with excessive reactive oxygen species production, endothelial dysfunction, thrombosis, and inflammation. Platelets are critical mediators of thromboinflammation during reperfusion injury and a hyperactive platelet phenotype may contribute to an exaggerated IR injury response. This is particularly relevant to diabetes which is characteristically associated with hyperactive platelets, significantly worse IR injury, increased organ damage, and increased risk of death. However, the mechanisms underlying vulnerability to IR injury in diabetic individuals is not well defined, nor the role of diabetic platelets in this process. This review summarizes recent progress in understanding the role of platelets in promoting microvascular dysfunction and inflammation in the context of IR injury. Furthermore, the authors discuss aspects of the thromboinflammatory function of platelets that are dysregulated in diabetes. They conclude that diabetes likely enhances the capacity of platelets to mediate microvascular thrombosis and inflammation during IR injury, which has potentially important implications for the future design of antiplatelet agents that can reduce microvascular dysfunction and inflammation. 2018 by Thieme Medical Publishers, Inc.
-
Vaidya, Kaivan; Arnott, Clare; Martez, Gonzalo J.; Ng, Bernard H.K.; McCormack, Samuel R.; Sullivan, David R.; Celermajer, David S.; Patel, SanjayObjectives: The authors sought to evaluate the plaque-modifying effects of low-dose colchicine therapy plus optimal medical therapy (OMT) in patients post-acute coronary syndrome (ACS), as assessed by coronary computed tomography angiography (coronary CTA). Background: Colchicine therapy has been postulated to have beneficial anti-inflammatory effects in patients with ACS, translating into reduction in future adverse cardiovascular events. However, whether favorable plaque modification underpins this is yet unproven. Methods: In this prospective nonrandomized observational study of 80 patients with recent ACS (<1 month), patients received either 0.5 mg/day colchicine plus OMT or OMT alone and were followed for 1 year. Our primary outcome was change in low attenuation plaque volume (LAPV), a marker of plaque instability on coronary CTA and robust predictor of adverse cardiovascular events. Secondary outcomes were changes in other coronary CTA measures and in high-sensitivity C-reactive protein (hsCRP). Results: Mean duration of follow-up was 12.6 months; mean age was 57.4 years. Colchicine therapy significantly reduced LAPV (mean 15.9 mm3 [?40.9%] vs. 6.6 mm3 [?17.0%]; p = 0.008) and hsCRP (mean 1.10 mg/l [?37.3%] vs. 0.38 mg/l [?14.6%]; p < 0.001) versus controls. Reductions in total atheroma volume (mean 42.3 mm3 vs. 26.4 mm3; p = 0.28) and low-density lipoprotein levels (mean 0.44 mmol/l vs. 0.49 mmol/l; p = 0.21) were comparable in both groups. With multivariate linear regression, colchicine therapy remained significantly associated with greater reduction in LAPV (p = 0.039) and hsCRP (p = 0.004). There was also a significant linear association (p < 0.001) and strong positive correlation (r = 0.578) between change in LAPV and hsCRP. Conclusions: Our findings suggest, for the first time, that low-dose colchicine therapy favorably modifies coronary plaque, independent of high-dose statin intensification therapy and substantial low-density lipoprotein reduction. The improvements in plaque morphology are likely driven by the anti-inflammatory properties of colchicine, as demonstrated by reductions in hsCRP, rather than changes in lipoproteins. Colchicine may be beneficial as an additional secondary prevention agent in patients post-ACS if validated in future studies. 2018
-
Degendorfer, Georg; Chuang, Christine Y.; Mariotti, Michele; Hammer, Astrid; Hoefler, Gerald; H?gglund, Per Mten; Malle, Ernst; Wise, Steven G.; Davies, Michael J.Elastin is an abundant extracellular matrix protein in elastic tissues, including the lungs, skin and arteries, and comprises 3057% of the aorta by dry mass. The monomeric precursor, tropoelastin (TE), undergoes complex processing during elastogenesis to form mature elastic fibres. Peroxynitrous acid (ONOOH), a potent oxidising and nitrating agent, is formed in vivo from superoxide and nitric oxide radicals. Considerable evidence supports ONOOH formation in the inflamed artery wall, and a role for this species in the development of human atherosclerotic lesions, with ONOOH-damaged extracellular matrix implicated in lesion rupture. We demonstrate that TE is highly sensitive to ONOOH, with this resulting in extensive dimerization, fragmentation and nitration of Tyr residues to give 3-nitrotyrosine (3-nitroTyr). This occurs with equimolar or greater levels of oxidant and increases in a dose-dependent manner. Quantification of Tyr loss and 3-nitroTyr formation indicates extensive Tyr modification with up to two modified Tyr per protein molecule, and up to 8% conversion of initial ONOOH to 3-nitroTyr. These effects were modulated by bicarbonate, an alternative target for ONOOH. Inter- and intra-protein di-tyrosine cross-links have been characterized by mass spectrometry. Examination of human atherosclerotic lesions shows colocalization of 3-nitroTyr with elastin epitopes, consistent with TE or elastin modification in vivo, and also an association of 3-nitroTyr containing proteins and elastin with lipid deposits. These data suggest that exposure of TE to ONOOH gives marked chemical and structural changes to TE and altered matrix assembly, and that such damage accumulates in human arterial tissue during the development of atherosclerosis. 2017 Elsevier Inc.
-
Martez, Gonzalo J.; Celermajer, David S.; Patel, SanjayAtherosclerosis is considered a chronic inflammatory disease of the arterial wall. Recently, compelling evidence has arisen for the role of monocytes and neutrophils and a particular protein complex that resides within these cells the NLRP3 inflammasome in atherosclerosis-associated inflammation. It is now also known that cholesterol crystals are present through all stages of atherosclerosis and can activate the NLRP3 inflammasome within these inflammatory cells to produce interleukin 1? and interleukin 18 key mediators in the inflammatory cascade that drive plaque progression and instability. In this review, we describe the role of monocytes/macrophages and neutrophils in atherosclerosis, outline mechanisms of activation of the NLRP3 inflammasome in the setting of atherosclerosis-associated inflammation and discuss potential therapies that specifically target the NLRP3 inflammasome and/or its downstream mediators in atherosclerosis, with a particular focus on the emerging role of colchicine. 2017 Elsevier B.V.
-
Thompson, Peter Lindsay; Mark Nidorf, S.[No abstract available]
-
Filipe, Elysse C.; Santos, Miguel; Hung, Juichien; Lee, Bob S.L.; Yang, Nianji; Chan, Alex H.P.; Ng, Martin K.C.; Rnjak-Kovacina, Jelena; Wise, Steven G.Synthetic vascular grafts for small diameter revascularization are lacking. Clinically available conduits expanded polytetrafluorethylene and Dacron fail acutely due to thrombosis and in the longer term from neointimal hyperplasia. We report the bioengineering of a cell-free, silk-based vascular graft. In vitro we demonstrate strong, elastic silk conduits that support rapid endothelial cell attachment and spreading while simultaneously resisting blood clot and fibrin network formation. In vivo rat studies show complete graft patency at all time points, rapid endothelialization, and stabilization and contraction of neointimal hyperplasia. These studies show the potential of silk as an off-the-shelf small diameter vascular graft. 2018 The Authors
-
Seimon, Radhika V.; Wild-Taylor, Anthony L.; Gibson, A. A.; Harper, Claudia; McClintock, Sally; Fernando, Hamish Alexander; Hsu, Michelle S.H.; Da Luz, Felipe Q.; Keating, Shelley E.; Johnson, Nathan A.; Grieve, Stuart M.; Markovic, Tania P.; Caterson, Ian Douglas; Byrne, Nuala M.; Sainsbury, Amanda J.With obesity being a leading cause of preventable death, it is vital to understand how best to identify individuals with greater risk of metabolic disease, especially those with high visceral adipose tissue (VAT). This study aimed to determine whether three commonly used waist circumference (WC) measurement sites could provide accurate estimations of VAT, as determined by magnetic resonance imaging (MRI), which is a gold standard for measuring VAT, in postmenopausal women with obesity. VAT volume was measured by MRI of the total abdomen in 97 women aged 57.7 0.4 years (mean SEM), mean body mass index 34.5 0.2 kg/m2. WC was measured at the midpoint between the lowest rib and the iliac crest (WC<inf>mid</inf>), the narrowest point of the torso (WC<inf>narrow</inf>), and at the level of the umbilicus (WC<inf>umbilicus</inf>). WC differed significantly according to measurement site, with WC<inf>narrow</inf> (102.1 0.7 cm) < WC<inf>mid</inf> (108.3 0.7 cm) < WC<inf>umbilicus</inf> (115.7 0.8 cm) (p < 0.001). WC<inf>mid</inf>, WC<inf>narrow</inf> and WC<inf>umbilicus</inf> were all significantly correlated with VAT, as measured by MRI (r = 0.581, 0.563 and 0.390, respectively; p < 0.001 for all), but the relationships between WC<inf>mid</inf> or WC<inf>narrow</inf> and VAT determined by MRI were stronger than for WC<inf>umbilicus</inf>. Measurement of either WC<inf>mid</inf> or WC<inf>narrow</inf> provides valid estimates of VAT in postmenopausal women with obesity, with WC<inf>narrow</inf> being favoured in light of its greater ease and speed of measurement in this population. 2018 by the authors. Licensee MDPI, Basel, Switzerland.
-
Santos, Miguel; Michael, Praveesuda Lorwattanapongsa; Filipe, Elysse C.; Chan, Alex H.P.; Hung, Juichien; Tan, Richard P.; Lee, Bob S.L.; Huynh, Minh D.; Hawkins, Clare L.; Waterhouse, Anna; Bilek, Marcela M.M.; Wise, Steven G.Multifunctional nanoparticles are increasingly employed to improve biological efficiency in medical imaging, diagnostics, and treatment applications. However, even the most well-established nanoparticle platforms rely on multiple-step wet-chemistry approaches for functionalization often with linkers, substantially increasing complexity and cost, while limiting efficacy. Plasma dust nanoparticles are ubiquitous in space, commonly observed in reactive plasmas, and long regarded as detrimental to many manufacturing processes. As the bulk of research to date has sought to eliminate plasma nanoparticles, their potential in theranostics has been overlooked. Here we show that carbon-activated plasma-polymerized nanoparticles (nanoP3) can be synthesized in dusty plasmas with tailored properties, in a process that is compatible with scale up to high throughput, low-cost commercial production. We demonstrate that nanoP3 have a long active shelf life, containing a reservoir of long-lived radicals embedded during their synthesis that facilitate attachment of molecules upon contact with the nanoparticle surface. Following synthesis, nanoP3 are transferred to the bench, where simple one-step incubation in aqueous solution, without the need for intermediate chemical linkers or purification steps, immobilizes multiple cargo that retain biological activity. Bare nanoP3 readily enter multiple cell types and do not inhibit cell proliferation. Following functionalization with multiple fluorescently labeled cargo, nanoP3 retain their ability to cross the cell membrane. This paper shows the unanticipated potential of carbonaceous plasma dust for theranostics, facilitating simultaneous imaging and cargo delivery on an easily customizable, functionalizable, cost-effective, and scalable nanoparticle platform. 2018 American Chemical Society.
-
Butera, Diego; Passam, Freda H.; Ju, Lining Arnold; Cook, Kristina M.; Woon, Heng; Aponte-Santamar, Camilo; Gardiner, Elizabeth E.; Davis, Amanda Katherine; Murphy, Deirdre A.; Bronowska, Agnieszka Katarzyna; Luken, Brenda M.; Baldauf, Carsten; Jackson, Shaun P.; Andrews, Robert K.; Grer, Frauke; Hogg, Philip J.Force-dependent binding of platelet glycoprotein Ib (GPIb) receptors to plasma von Willebrand factor (VWF) plays a key role in hemostasis and thrombosis. Previous studies have suggested that VWF activation requires force-induced exposure of the GPIb binding site in the A1 domain that is autoinhibited by the neighboring A2 domain. However, the biochemical basis of this "mechanopresentation" remains elusive. From a combination of protein chemical, biophysical, and functional studies, we find that the autoinhibition is controlled by the redox state of an unusual disulfide bond near the carboxyl terminus of the A2 domain that links adjacent cysteine residues to form an eight-membered ring. Only when the bond is cleaved does the A2 domain bind to the A1 domain and block platelet GPIb binding. Molecular dynamics simulations indicate that cleavage of the disulfide bond modifies the structure and molecular stresses of the A2 domain in a long-range allosteric manner, which provides a structural explanation for redox control of the autoinhibition. Significantly, the A2 disulfide bond is cleaved in ?75% of VWF subunits in healthy human donor plasma but in just ?25% of plasma VWF subunits from heart failure patients who have received extracorporeal membrane oxygenation support. This suggests that the majority of plasma VWF binding sites for platelet GPIb are autoinhibited in healthy donors but are mostly available in heart failure patients. These findings demonstrate that a disulfide bond switch regulates mechanopresentation of VWF. 2018 The Authors, some rights reserved.
-
Chung, Kevin; Strange, G. A.; Codde, Jim P.; Celermajer, David S.; Scalia, Gregory M.; Playford, David A.Pulmonary hypertension (PH) is common, under diagnosed and associated with a high mortality. There are significant delays in the diagnosis of pulmonary hypertension leading to increased morbidity and delays in the initiation of treatment. Once PH is diagnosed, establishing the degree of pulmonary vascular resistance (PVR) enables clinicians to broadly divide the underlying pathology into pre-capillary or post-capillary causes, a crucial step in tailoring management. Pulmonary hypertension is most commonly due to left heart disease (PH-LHD) and echocardiography (echo) is the most widely accessible investigation in its diagnosis. Regardless of the underlying pathophysiology of LHD, the sequelae lead to pressure overload on the left heart and a reactive increase in pulmonary pressures. In this review article, we will discuss the prevalence of PH, examine the pathophysiology of PH-LHD, establish how echo can be used to identify patients with PH-LHD and discuss surrogate echo markers of PVR. 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ)
-
Morton, Jamie; Bao, Shishan San; Vanags, Laura Z.; Tsatralis, Tania; Ridiandries, Anisyah; Siu, David Chung Wah; Ng, Kwong Man; Tan, Joanne Tsui Ming; Celermajer, David S.; Ng, Martin K.C.; Bursill, C. A.Preclinical studies have shown benefit of apolipoprotein A-I (apoA-I)/high-density lipoprotein (HDL) raising in atherosclerosis; however, this has not yet translated into a successful clinical therapy. Our studies demonstrate that apoA-I raising is more effective at reducing early-stage atherosclerosis than late-stage disease, indicating that the timing of HDL raising is a critical factor in its atheroprotective effects. To date, HDL-raising clinical trials have only been performed in aged patients with advanced atherosclerotic disease. Our findings therefore provide insight, related to important temporal aspects of HDL raising, as to why the clinical trials have thus far been largely neutral. 2018 The Authors
-
Gu, Yulong; Doughty, Rob N.; Freedman, Ben Ben; Kennelly, John; Warren, James R.; Harwood, Matire Louise Ngarongoa; Hulme, Richard; Paltridge, Chris; Teh, Ruth O.Y.; Rolleston, Anna K.; Walker, Natalie K.Background: Atrial fibrillation (AF) is a major risk factor for ischaemic stroke and cardiovascular events. In New Zealand (NZ), M?ori (indigenous New Zealanders) and Pacific people experience higher rates of AF compared with non-M?ori/non-Pacific people. Aim: To describe a primary care population with AF in NZ. Stroke risk and medication adherence according to ethnicity are also detailed. Methods: Electronic medical records for adults (?20 years, n = 135 840, including 19 918 M?ori and 43 634 Pacific people) enrolled at 37 NZ general practices were analysed for AF diagnosis and associated medication prescription information. Results: The overall prevalence of non-valvular AF (NVAF) in this population was 1.3% (1769), and increased with age (4.4% in people ?55 years). M?ori aged ?55 years were more likely to be diagnosed with NVAF (7.3%) than Pacific (4.0%) and non-M?ori/non-Pacific people (4.1%, P < 0.001). M?ori and Pacific NVAF patients were diagnosed with AF 10 years earlier than non-M?ori/non-Pacific patients (median age of diagnosis: M?ori = 60 years, Pacific = 61 years, non-M?ori/non-Pacific = 71 years, P < 0.001). Overall, 67% of NVAF patients were at high risk for stroke (CHA<inf>2</inf>DS<inf>2</inf>-VASc ? 2) at the time of AF diagnosis. Almost half (48%) of M?ori and Pacific NVAF patients aged <65 years were at high risk for stroke, compared with 22% of non-M?ori/non-Pacific (P < 0.001). Irrespective of ethnic group, adherence to AF medication was suboptimal in those NVAF patients with a high risk of stroke or with stroke history. Conclusion: AF screening and stroke thromboprophylaxis in M?ori and Pacific people could start below the age of 65 years in NZ. 2017 Royal Australasian College of Physicians
-
Lowres, Nicole; Mulcahy, Georgina; Jin, Kai; Gallagher, Robyn D.; Neubeck, Lis; Freedman, Ben BenPostoperative atrial fibrillation (POAF) is associated with increased stroke risk and mortality post-discharge. POAF is often considered transient; however, recurrence is likely under-recognized as symptoms are an unreliable guide. Surveillance post-discharge may identify asymptomatic POAF recurrences in patients discharged in sinus rhythm. Therefore, we performed a systematic review and meta-analysis of studies investigating POAF recurrence post-discharge, in patients with new-onset POAF following cardiac surgery who reverted to sinus rhythm prior to discharge. Two independent reviewers searched medical databases, clinical trial registries, reference lists and the Internet. After screening from 6525 studies, 8 studies were identified (n = 1157 participants, mean age 66 10 years and 73% men). Monitoring methods included the following: telemetry during twice-daily exercise sessions (n = 2), continuous telemetry for 3 weeks (n = 1), daily 20-s electrocardiography (ECG) using wearable event recorder (n = 1), 30-s single-lead ECG, 4 times/day (n = 1) and implanted continuous monitoring (n = 2). The incidence rate of POAF recurrence identified through non-invasive monitoring in the first 4 weeks post-discharge was 28.3% [confidence interval (CI) 23.0-33.6%]; recurring 12 5 days (mean SD) post-surgery. The incidence rate identified through implanted continuous monitoring was 61-100% within 2 years. Between 40% and 93% of episodes were asymptomatic. In one small study reporting stroke risk, 8 of 10 patients with recurrence were guideline-indicated (CHA2DS2-VASc score >2) for oral anticoagulation for stroke prevention. Monitoring for POAF recurrence post-hospital discharge identifies significant numbers of early asymptomatic recurrences in patients at high risk of stroke who may benefit from anticoagulation for stroke prevention. More intense monitoring is more likely to identify POAF recurrence. Future research is required to investigate the prognostic significance of POAF recurrence, especially stroke and mortality risk. The Author 2017.
-
Pan, Gary J.; Rayner, Benjamin Saul; Zhang, Yunjia; Van Reyk, David M.; Hawkins, Clare L.Atherosclerosis is characterised by the infiltration of macrophages at sites of inflammation within the vessel wall and the release of myeloperoxidase (MPO), which forms hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN). HOCl is a damaging oxidant implicated in the development of atherosclerosis. Preferential formation of HOSCN occurs under conditions where thiocyanate ions are elevated, as is the case in smokers. HOSCN reacts selectively with thiols, which can result in more enzyme inactivation and damage than HOCl at susceptible sites, which may contribute to atherosclerosis in smokers. In this study, we show that exposure of macrophages to HOSCN results in a time- and dose-dependent increase in the mRNA expression and release of pro-inflammatory cytokines and chemokines, including monocyte chemotactic protein 1, tumour necrosis factor alpha, and interleukins 6, 8 and 1?. At high oxidant concentrations (>200 ?M), a significant loss of cellular thiols and increased cell death is observed. HOSCN-induced cytokine/chemokine expression and cell death were decreased on pharmacological inhibition of nuclear factor kappa B. These data highlight a pathway by which HOSCN could promote inflammation and the development of atherosclerosis, in the presence of supra-physiological levels of the precursor thiocyanate, which are achievable by cigarette smoking. 2018 Elsevier Inc.
-
Tan, Richard P.; Chan, Alex H.P.; Lennartsson, Katarina; Miravet, Maria M.; Lee, Bob S.L.; Rnjak-Kovacina, Jelena; Clayton, Zoe E.; Cooke, John P.; Ng, Martin K.C.; Patel, Sanjay; Wise, Steven G.Background: Induced pluripotent stem-cell derived endothelial cells (iPSC-ECs) can be generated from any somatic cell and their iPSC sources possess unlimited self-renewal. Previous demonstration of their proangiogenic activity makes them a promising cell type for treatment of ischemic injury. As with many other stem cell approaches, the low rate of in-vivo survival has been a major limitation to the efficacy of iPSC-ECs to date. In this study, we aimed to increase the in-vivo lifetime of iPSC-ECs by culturing them on electrospun polycaprolactone (PCL)/gelatin scaffolds, before quantifying the subsequent impact on their proangiogenic function. Methods: iPSC-ECs were isolated and stably transfected with a luciferase reporter to facilitate quantification of cell numbers and non-invasive imaging in-vivo PCL/gelatin scaffolds were engineered using electrospinning to obtain woven meshes of nanofibers. iPSC-ECs were cultured on scaffolds for 7 days. Subsequently, cell growth and function were assessed in vitro followed by implantation in a mouseback subcutaneous model for 7 days. Results: Using a matrix of conditions, we found that scaffold blends with ratios of PCL:gelatin of 70:30 (PG73) spun at high flow rates supported the greatest levels of iPSC-EC growth, retention of phenotype, and function in vitro. Implanting iPSC-ECs seeded on PG73 scaffolds in vivo improved their survival up to 3 days, compared to cells directly injected into control wounds, which were no longer observable within 1 h. Enhanced engraftment improved blood perfusion, observed through non-invasive laser Doppler imaging. Immunohistochemistry revealed a corresponding increase in host angiogenic mechanisms characterized by the enhanced recruitment of macrophages and the elevated expression of proangiogenic cytokines vascular endothelial growth factor and placental growth factor. Conclusions: Knowledge of these mechanisms combined with a deeper understanding of the scaffold parameters influencing this function provides the groundwork for optimizing future iPSC-EC therapies utilizing engraftment platforms. The development of combined scaffold and iPSC-EC therapies could ultimately improve therapeutic angiogenesis and the treatment of ischemic injury. 2018 The Author(s).
-
Celermajer, David S.[No abstract available]
-
Khoo, Rachel; Jansen, Shirley JaneThe diabetic heel ulcer (DHU) represents a reconstructive challenge to clinicians and the multidisciplinary team alike. It is traditionally viewed as a condition that is inherently difficult to treat due to the intrinsic anatomical vulnerabilities of the heel. In addition to this, several factors are associated with poorer end outcomesnamely, that of major amputation. These include peripheral vascular disease, infection/osteomyelitis and the size of the ulcer itself. In light of the significant morbidity, economic burden and mortality seen in this cohort of patients, this review aims to explore current treatment modalities that have been undertaken. Literature in this field has mostly been confined to a handful of small case studies, some of which reflect novel, multimodal approaches, and promising results. Management with osteotomy, flap reconstruction and acellular dermal matrices, amongst other options, is covered within this review. 2018 Medicalhelplines.com Inc and John Wiley & Sons Ltd
-
Carroll, Luke; Pattison, David I.; Davies, Justin Bryan; Anderson, Robert F.; Lez-Alarc, Camilo; Davies, Michael J.Oxidative damage is a common process in many biological systems and proteins are major targets for damage due to their high abundance and very high rate constants for reaction with many oxidants (both radicals and two-electron species). Tryptophan (Trp) residues on peptides and proteins are a major sink for a large range of biological oxidants as these side-chains have low radical reduction potentials. The resulting Trp-derived indolyl radicals (Trp) have long lifetimes in some circumstances due to their delocalized structures, and undergo only slow reaction with molecular oxygen, unlike most other biological radicals. In contrast, we have shown previously that Trp undergo rapid dimerization. In the current study, we show that Trp also undergo very fast reaction with superoxide radicals, O<inf>2</inf> ?, with k 12 109 M?1 s?1. These values do not alter dramatically with peptide structure, but the values of k correlate with overall peptide positive charge, consistent with positive electrostatic interactions. These reactions compete favourably with Trp dimerization and O<inf>2</inf> addition, indicating that this may be a major fate in some circumstances. The Trp + O<inf>2</inf> ? reactions occur primarily by addition, rather than electron transfer, with this resulting in high yields of Trp-derived hydroperoxides. Subsequent degradation of these species, both stimulated and native decay, gives rise to N-formylkynurenine, kynurenine, alcohols and diols. These data indicate that reaction of O<inf>2</inf> ? with Trp should be considered as a major pathway to Trp degradation on peptides and proteins subjected to oxidative damage. 2018 Elsevier Inc.
-
Pears, Suzanne; Makris, Angela; Hennessy, AnnemarieThis review summarizes the literature to date on the subject of the chronobiology of blood pressure in pregnancy, and more specifically, in the common disease state of high blood pressure in pregnancy or preeclampsia. While the guidelines for treating hypertension in pregnancy use absolute measures to start treatment, they do not take into account the important rhythms of hypertension including nighttime and daytime readings. These variations are likely to have strong impacts on pregnancy outcomes, risk and long-term hypertension risk. 2018
-
Kakall, Zohra Mohtat; Pilowsky, Paul M.; Farnham, M. M. J.Intermittent hypoxia causes a persistent increase in sympathetic activity that progresses to hypertension in chronic conditions such as obstructive sleep apnea. Pituitary adenylate cyclase-activating polypeptide (PACAP) is an excitatory neurotransmitter that causes long-lasting sympathetic excitation. We aimed to determine if intermittent activation of the rostral ventrolateral medulla (RVLM) causes PACAP-mediated elevation of sympathetic nerve activity, termed sympathetic long-term facilitation (sLTF). The role of PACAP in mediating sLTF in response to intermittent activation of the RVLM was investigated in urethane-anaesthetized and artificially ventilated rats (n = 65, Sprague-Dawley). Bilateral RVLM microinjections of the PACAP type 1 receptor/vasoactive intestinal polypeptide receptor type 2 receptor antagonist PACAP-(6-38) [n = 6, change (?): -16.4 6.5%) or an ionotropic glutamate antagonist, kynurenate (n = 6, ?:-7.2 2.3%), blocked the development of acute intermittent hypoxia-induced sLTF (n = 6, ?: 49.2 14.2%). Intermittent RVLM microinjections of glutamate caused sLTF (n = 5, ?: 56.9 14.7%) that was abolished by PACAP-(6-38) pretreatment (n = 5, ?:-1.2 4.7%). Conversely, intermittent microinjections of PACAP in the RVLM did not elicit sLTF. Intermittent bilateral disinhibition of the RVLM by microinjection of ?-aminobutyric acid in the caudal ventrolateral medulla did not elicit sLTF. Direct activation of RVLM neurons is crucial for the development of sLTF. PACAP and glutamate act synergistically in the RVLM, with both being necessary for the sLTF response. We found that activation of glutamate but not PACAP receptors is necessary and sufficient to generate sLTF, even in the absence of intermittent hypoxia. Our results demonstrate that PACAP within the RVLM may contribute to the development of obstructive sleep apnea -induced hypertension. NEW & NOTEWORTHY Pharmacological blockade of either pituitary adenylate cyclase-activating polypeptide (PACAP) or ionotropic glutamate receptors in the rostral ventrolateral medulla prevents development of sympathetic long-term facilitation. PACAP receptor inhibition prevents the occurrence of hypoxia-induced peripheral chemoreflex sensitization. Thus, PACAP receptors may be a potential therapeutic target serving to reduce heightened sympathetic tone and hypersensitized cardiovascular reflexes. 2018 the American Physiological Society.
