A5072222896- Nitric Oxide and Endothelin Effects
- Mitochondrial Function and Pathology
- Eicosanoids and Hypertension Pharmacology
- Hormonal Regulation and Hypertension
- Redox biology and oxidative stress
- Receptor Mechanisms and Signaling
- Adipose Tissue and Metabolism
- Renin-Angiotensin System Studies
- Sulfur Compounds in Biology
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Pulmonary Hypertension Research and Treatments
- Birth, Development, and Health
- Cardiac electrophysiology and arrhythmias
- Ion channel regulation and function
- Melanoma and MAPK Pathways
- Biochemical effects in animals
- Sepsis Diagnosis and Treatment
- Metabolism and Genetic Disorders
- Cancer, Hypoxia, and Metabolism
- Anesthesia and Neurotoxicity Research
- Neuroscience and Neuropharmacology Research
- Coenzyme Q10 studies and effects
- Hemodynamic Monitoring and Therapy
- Regulation of Appetite and Obesity
- Ion Transport and Channel Regulation
King's College London
2013-2023
British Heart Foundation
2012-2023
St Thomas' Hospital
2010-2023
Queen Mary University of London
2020
National Institute for Health Research
2020
William Harvey Research Institute
2020
St. Thomas Hospital
2014
Kings Health Partners
2013
Bogomoletz Institute of Physiology
2006-2010
National Academy of Sciences of Ukraine
2010
Dysregulated blood pressure control leading to hypertension is prevalent and a risk factor for several common diseases. Fully understanding regulation offers the possibility of developing rationale therapies alleviate associated disease risks. Although hydrogen sulfide (H2S) well-established endogenous vasodilator, molecular basis its blood-pressure lowering action incompletely understood. H2S-dependent vasodilation in vivo was mediated by it catalyzing formation an activating interprotein...
Significance The Mediterranean diet is characterized by consumption of unsaturated fats with vegetables rich in nitrite and nitrate, resulting endogenous formation nitro fatty acids. These reactive lipids adduct to soluble epoxide hydrolase, inhibiting it lower blood pressure. Mice genetically engineered be resistant this adductive inhibition had high pressure basally their hydrolase activity was fully acid supplied directly or generated via the diet. Similarly lowered abrogated cardiac...
Protein kinase G (PKG) is activated by nitric oxide (NO)-induced cGMP binding or alternatively oxidant-induced interprotein disulfide formation. We found preactivation with attenuated PKG oxidation. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) blockade of production increased to 13 ± 2% and 29±4% total in aorta mesenteries, respectively. This was potentially anomalous, because we observed 2.7-fold higher NO levels than mesenteries; consequently, had anticipated that ODQ would induce...
Sepsis is a common life-threatening clinical syndrome involving complications as result of severe infection. A cardinal feature sepsis inflammation that results in oxidative stress. wild-type mice induced activation cGMP-dependent protein kinase 1 alpha (PKG Iα), which increased blood vessel dilation and permeability, also lowered cardiac output. These responses are typical features their combined effect lowering pressure. This hypotension, hallmark sepsis, resulted underperfusion end...
Although nitroglycerin has remained in clinical use since 1879, the mechanism by which it relaxes blood vessels to lower pressure remains incompletely understood. Nitroglycerin undergoes metabolism that generates several reaction products, including oxidants, and this bioactivation process is essential for vasodilation. Protein kinase G (PKG) mediates classic nitric oxide-dependent vasorelaxation, but 1α isoform also independently activated oxidation involves interprotein disulfide formation...
The prevalence of obesity among pregnant women is increasing. Evidence from human cohort studies and experimental animals suggests that offspring cardiovascular metabolic function compromised through early life exposure to maternal obesity. Previously, we reported juvenile obese rats develop sympathetically mediated hypertension associated with neonatal hyperleptinemia. We have now addressed the hypothesis raised leptin in immediate postnatal period plays a causal role. Pups lean...
Angiogenesis is essential for tissue development, wound healing and perfusion, with its dysregulation linked to tumorigenesis, rheumatoid arthritis heart disease. Here we show that pro-angiogenic stimuli couple NADPH oxidase-dependent generation of oxidants catalyse an activating intermolecular-disulphide between regulatory-RIα subunits protein kinase A (PKA), which stimulates PKA-dependent ERK signalling. This crucial blood vessel growth as 'redox-dead' Cys17Ser RIα knock-in mice fully...
Abstract The Frank–Starling mechanism allows the amount of blood entering heart from veins to be precisely matched with pumped out arterial circulation. As fills during diastole, myocardium is stretched and oxidants are produced. Here we show that protein kinase G Iα (PKGIα) oxidant-activated stretch this form selectively phosphorylates cardiac phospholamban Ser16—a site important for diastolic relaxation. We find hearts Cys42Ser PKGIα knock-in (KI) mice, which resistant oxidation, have...
Pulmonary hypertension (PH) is a chronic vascular disease characterized, among other abnormalities, by hyperproliferative smooth muscle cells and perturbed cellular redox metabolic balance. Oxidants induce cell cycle arrest to halt proliferation; however, little known about the redox-regulated effector proteins that mediate these processes. Here, we report novel kinase-inhibitory disulfide bond in cyclin D-CDK4 (cyclin-dependent kinase 4) investigate its role proliferation PH.
Sepsis and sepsis-associated multiorgan failure represent the major cause of mortality in intensive care units worldwide. Cardiovascular dysfunction, a key component sepsis pathogenesis, has received much research interest, although translatability remains severely limited. There is critical need for more comprehensive preclinical models, with clinically relevant end points, such as microvascular perfusion. The purpose this study was to compare microcirculatory blood flow measurements, using...
The kinase p38α MAPK (p38α) plays a pivotal role in many biological processes. is activated by canonical upstream kinases that phosphorylate the activation region. purpose of our study was to determine whether such may depend on redox-sensing cysteines within p38α. and formed disulfide-bound heterodimer with MAP2K3 (MKK3) rat cardiomyocytes isolated hearts exposed H2O2. This disulfide sensitive reduction mercaptoethanol enhanced thioredoxin-reductase inhibitor auranofin. We predicted Cys-119...
Although it has long been recognized that smooth muscle Na/K ATPase modulates vascular tone and blood pressure (BP), the role of its accessory protein phospholemman not characterized. The aim this study was to test hypothesis phosphorylation regulates in vitro mechanism plays an important modulation function BP experimental models vivo humans.In mouse studies, knock-in mice (PLM3SA; [FXYD1] which 3 sites on serines 63, 68, 69 are mutated alanines), is rendered unphosphorylatable, were used...
Diet-induced obesity in rat pregnancy has been shown previously to be associated with consistently raised blood pressure the offspring, attributed sympathetic over-activation, but relative contributions this phenotype of maternal versus dietary fat is unknown. Sprague-Dawley female rats were fed either a control (4.3% fat, n = 11) or lard-enriched (23.6% 16) chow 10 days prior mating, throughout and lactation. In conscious adult (9-month-old) offspring cardiovascular parameters measured...
Aberrant proliferation of mesangial cells (MCs) is a key finding in progressive glomerular disease. TH1177 small molecule that has been shown to inhibit low-voltage activated T-type Ca(2+) channels (TCCs). The current study investigates the effect on MC vitro and vivo. channel inhibition primary rat was studied using microculture tetrazolium assay by measuring bromodeoxyuridine incorporation. In vivo, rats with Thy1 nephritis were treated or vehicle. Glomerular injury average cell number...
Significance This study demonstrates that oxidation of protein kinase G Iα (PKGIα) to its disulfide-activated state occurs in pulmonary arteries during chronic hypoxia, and this is a protective event limits progression hypertension by at least two mechanisms. Firstly, it induces vasodilation counters offsets maladaptive vasoconstriction and, secondly, disulfide PKGIα preventing growth fibrosis signaling. Consistent with being protective, administration polysulfides mice which increased the...
Nitro-oleate (10-nitro-octadec-9-enoic acid), which inhibits soluble epoxide hydrolase (sEH) by covalently adducting to C521, increases the abundance of epoxyeicosatrienoic acids (EETs) that can be health promoting, for example lowering blood pressure or their anti-inflammatory actions. However, perhaps consistent with impact on angiogenesis, in EETs may exacerbate progression some cancers. To assess this, Lewis lung carcinoma (LLc1) cells were exposed oleate nitro-oleate, latter inhibiting...
Protein kinase G (PKG) Iα is the end-effector that mediates nitric oxide (NO)-dependent and oxidant-dependent vasorelaxation to maintain blood pressure during health. A hallmark of cardiovascular disease attenuated NO production, which in part caused by Synthase (NOS) uncoupling, turn increases oxidative stress because superoxide generation. NOS uncoupling promotes PKG oxidation interprotein disulfide state, likely mediated superoxide-derived hydrogen peroxide, NO-cyclic guanosine...