Jacqueline Ohanian

University of Manchester

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Co-Authors

Vasken Ohanian

University of Manchester

Anthony M. Heagerty

University of Manchester

Sophie N. Saxton

University of Manchester

Sarah Withers

University of British Columbia

Donald T. Ward

University of Manchester

Robert Aldous

St George’s University Hospitals NHS Foundation Trust

Linda Shaw

University of Manchester

Simon P. Forman

University of Manchester

Ann E. Canfield

University of Manchester

Stephen F. Vatner

Rutgers New Jersey Medical School

Cooperative Institutions

University of Manchester

Centre National de la Recherche Scientifique

Imperial College London

Manchester Academic Health Science Centre

University College London

Centro de Investigación Biomédica en Red

Manchester Royal Infirmary

Inserm

Amsterdam UMC Location VUmc

Goethe University Frankfurt

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Increase by lysophosphatidylcholines of smooth muscle Ca²⁺ sensitivity in α‐toxin‐permeabilized small mesenteric artery from the rat

British Journal of Pharmacology (1996)

Peter E. Jensen Jacqueline Ohanian Brian Stausbøl‐Grøn Niels Henrik Buus Christian Aalkjær

1 Pharmacological characterization of different lysophosphatidylcholines was performed based on their effect on the Ca2+ sensitivity of contraction in α-toxin-permeabilized rat mesenteric arteries. Furthermore, the effect of noradrenaline on [3H]-myristate-labelled lysophosphatidylcholine levels was assessed, to investigate whether lysophosphatidylcholines could be second messengers. 2 Palmitoyl or myristoyl L-α-lysophosphatidylcholine increased the sensitivity to Ca2+, whereas lysophosphatidylcholines containing other fatty acids had less or no effect. 3 L-α-phosphatidylcholine, L-α-glycerophosphorylcholine, palmitic acid, myristic acid and choline, potential metabolites of lysophosphatidylcholines, did not affect contractions. 4 Noradrenaline (GTP was required) and GTPγS increased the sensitivity to Ca2+, and GDP-β-S inhibited the effect of noradrenaline. Lysophosphatidylcholines, however, had no requirement for GTP and caused sensitization in the presence of GDP-β-S. 5 Calphostin C, a relatively specific protein kinase C inhibitor, did not affect contraction induced by Ca2+, but abolished the sensitizing effect of lysophosphatidylcholine. 6 Noradrenaline caused no measurable changes in the levels of [3H]-myristate-labelled phosphatidylcholine and lysophosphatidylcholine at 30 s and 5 min stimulation. 7 These results suggest that lysophosphatidylcholines can increase Ca2+ sensitivity through a G-protein-independent, but a protein kinase C-dependent mechanism. However, the role for lysophosphatidylcholines as messengers causing Ca2+ sensitization during stimulation with noradrenaline remains uncertain because no increase in [3H]-myristate labelled lysophosphatidylcholine could be measured during noradrenaline stimulation.

Lysophosphatidylcholine

Second messenger system

10.1111/j.1476-5381.1996.tb16721.x

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Citations (14)

Diacylglycerol kinase θ is translocated and phosphoinositide 3-kinase-dependently activated by noradrenaline but not angiotensin II in intact small arteries

Biochemical Journal (2000)

Anthony J. Walker Annette Draeger Brahim Houssa Wim J. van Blitterswijk Vasken Ohanian

Diacylglycerol (DG) kinase (DGK) phosphorylates the lipid second messenger DG to phosphatidic acid. We reported previously that noradrenaline (NA), but not angiotensin II (AII), increases membrane-associated DGK activity in rat small arteries [Ohanian and Heagerty (1994) Biochem. J. 300, 51-56]. Here, we have identified this DGK activity as DGKtheta, present in both smooth muscle and endothelial cells of these small vessels. Subcellular fractionation of artery homogenates revealed that DGKtheta was present in nuclear, plasma membrane (and/or Golgi) and cytosolic fractions. Upon NA stimulation, DGKtheta translocated towards the membrane and cytosol (155 and 153% increases relative to the control, respectively) at 30 s, followed by a return to near-basal levels at 5 min; AII was without effect. Translocation to the membrane was to both Triton-soluble and -insoluble fractions. NA, but not AII, transiently increased DGKtheta activity in immunoprecipitates (126% at 60 s). Membrane translocation and DGKtheta activation were regulated differently: NA-induced DGKtheta activation, but not translocation, was dependent on transient activation of phosphoinositide 3-kinase (PI 3-K). In addition, DGK activity co-immunoprecipitated with protein kinase B, a downstream effector of PI 3-K, and was increased greatly by NA stimulation. The rapid and agonist-specific activation of DGKtheta suggests that this pathway may have a physiological role in vascular smooth-muscle responses.

10.1042/0264-6021:3530129

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Citations (36)

Front & Back Matter

Journal of Vascular Research (2012)

Yanna Dantas Rattmann Eric Anselm Jong‐Hun Kim S. Dal-Ros Cyril Auger

10.1159/000341325

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Citations (0)

Conference Calendar

Journal of Vascular Research (2012)

Yanna Dantas Rattmann Eric Anselm Jong-Hun Kim S. Dal-Ros Cyril Auger

10.1159/000339548

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Non-receptor tyrosine kinases and the actin cytoskeleton in contractile vascular smooth muscle

The Journal of Physiology (2014)

Jacqueline Ohanian Maria Pieri Vasken Ohanian

The contractility of vascular smooth muscle cells within the walls of arteries is regulated by mechanical stresses and vasoactive signals. Transduction of these diverse stimuli into a cellular response occurs through many different mechanisms, one being reorganisation of the actin cytoskeleton. In addition to a structural role in maintaining cellular architecture it is now clear that the actin cytoskeleton of contractile vascular smooth muscle cells is a dynamic structure reacting to changes in the cellular environment. Equally clear is that disrupting the cytoskeleton or interfering with its rearrangement, has profound effects on artery contractility. The actin cytoskeleton associates with dense plaques, also called focal adhesions, at the plasma membrane of smooth muscle cells. Vasoconstrictors and mechanical stress induce remodelling of the focal adhesions, concomitant with cytoskeletal reorganisation. Recent work has shown that non-receptor tyrosine kinases and tyrosine phosphorylation of focal adhesion proteins such as paxillin and Hic-5 are important for actin cytoskeleton and focal adhesion remodelling and contraction.

Paxillin

PTK2

Contractility

Actin remodeling

10.1113/jphysiol.2014.284174

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Citations (21)

Evidence for a functional calcium-sensing receptor that modulates myogenic tone in rat subcutaneous small arteries

AJP Heart and Circulatory Physiology (2004)

Jacqueline Ohanian Kelly Gatfield Donald T. Ward Vasken Ohanian

Myogenic tone of small arteries is dependent on the presence of extracellular calcium (Ca(o)(2+)), and, recently, a receptor that senses changes in Ca(2+), the calcium-sensing receptor (CaR), has been detected in vascular tissue. We investigated whether the CaR is involved in the regulation of myogenic tone in rat subcutaneous small arteries. Immunoblot analysis using a monoclonal antibody against the CaR demonstrated its presence in rat subcutaneous arteries. To determine whether the CaR was functionally active, segments of artery (< 250 microm internal diameter) mounted in a pressure myograph with an intraluminal pressure of 70 mmHg were studied after the development of myogenic tone. Increasing Ca(o)(2+) concentration ([Ca(2+)](o)) cumulatively from 0.5 to 10 mM induced an initial constriction (0.5-2 mM) followed by dilation (42 +/- 5% loss of tone). The dose-dependent dilation was mimicked by other known CaR agonists including magnesium (1-10 mM) and the aminoglycosides neomycin (0.003-10 mM) and kanamycin (0.003-3 mM). PKC activation with the phorbol ester phorbol-12,13-dibutyrate (20nM) inhibited the dilation induced by high [Ca(2+)](o) or neomycin, whereas inhibition of PKC with GF109203X (10 microM) increased the responses to Ca(o)(2+) or neomycin, consistent with the role of PKC as a negative regulator of the CaR. We conclude that rat subcutaneous arteries express a functionally active CaR that may be involved in the modulation of myogenic tone and hence the regulation of peripheral vascular resistance.

Myograph

Neomycin

Electrical impedance myography

Myogenic contraction

10.1152/ajpheart.00739.2004

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Citations (73)

Calcium Sensitivity and Agonist-Induced Calcium Sensitization in Small Arteries of Young and Adult Spontaneously Hypertensive Rats

Hypertension (1997)

Linda Shaw Jacqueline Ohanian Anthony M. Heagerty

Abstract The sensitivity of the myofilaments to Ca 2+ is increased during agonist-induced contraction of vascular smooth muscle. Given the important contribution of vascular tone to the elevation of peripheral resistance observed in genetic hypertension, we have investigated whether alterations in myofilament Ca 2+ sensitivity occur in small arteries from spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) controls during the developmental and established phases of hypertension. Segments of mesenteric, renal, and femoral artery with an average lumen diameter <300 μm from 5- or 20-week-old rats were mounted in a wire myograph. Morphological measurements were made and the vessels permeabilized with Staphylococcus aureus α-toxin. Dose-response curves to increasing concentrations of Ca 2+ were obtained and the ability of 100 nmol/L endothelin-1 (ET-1) or 10 μmol/L norepinephrine (NE) in the presence of 10 μmol/L GTP to enhance tension in response to low Ca 2+ (pCa6.7) was determined. Systolic, diastolic, and mean blood pressures were higher in SHR than in WKY at 5 and 20 weeks. The media thickness:lumen diameter ratio was increased in mesenteric and femoral arteries from SHR compared with WKY at 5 and 20 weeks. There was no difference in media thickness:lumen diameter ratio in renal arteries or between 5- and 20-week animals in any vascular bed. The pCa curves were not different in mesenteric, renal, or femoral arteries from hypertensive compared with normotensive rats or between age groups, except in femoral arteries at 20 weeks, which exhibited a greater sensitivity to Ca 2+ in SHR. Tension developed in response to maximal Ca 2+ (pCa5.0) was greater in permeabilized mesenteric arteries from SHR compared with WKY at 20 weeks of age only; media stress was again similar in both strains but increased in older animals compared with younger animals in mesenteric arteries from WKY. The submaximal contraction induced by pCa6.7 was greater in femoral and renal than mesenteric arteries. GTP (10 μmol/L) augmented the tension developed to pCa6.7 in mesenteric arteries at 5 and 20 weeks and in renal arteries at 20 weeks. Addition of 100 nmol/L ET-1 or 10 μmol/L NE in the continued presence of GTP markedly increased tension in mesenteric arteries at 5 and 20 weeks. In renal arteries, 10 μmol/L NE enhanced Ca 2+ sensitivity in the presence of GTP in SHR at 5 and 20 weeks and WKY at 5 weeks. In femoral arteries, there was a tendency for ET-1 and NE to increase Ca 2+ sensitivity, but this increase was significant in WKY at 20 weeks (ET-1) and SHR at 5 weeks (NE) only. We have demonstrated that the sensitivity of the myofilaments to Ca 2+ and ET-1– or NE-induced Ca 2+ sensitization is not different in permeabilized small mesenteric, renal, or femoral arteries from SHR compared with WKY controls. Only in SHR mesenteric arteries at 20 weeks of age was there evidence of increased active tension in response to maximal Ca 2+ , despite structural differences, consistent with increased muscle mass in femoral arteries from SHR. We conclude that it is unlikely that a ubiquitous abnormality of the sensitivity of the contractile apparatus to Ca 2+ or agonist-induced Ca 2+ sensitization in vascular smooth muscle underlies the elevated total peripheral resistance associated with hypertension.

10.1161/01.hyp.30.3.442

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Citations (30)

P157Reversing adrenoceptor dysfunction in obese perivascular adipose tissue using exercise

Cardiovascular Research (2018)

Sophie N. Saxton Robert Aldous Sarah Withers Jacqueline Ohanian Anthony M. Heagerty

genotypes of hemostatic system.One patient (2,3%) had unfavorable heterozygous genotypes according to 5 studied variants predisposing to the development of thrombophilia; 8 (18%) had heterozygous genotypes of 4 SNP, 14 (32%) had heterozygous genotypes of 3 SNP, 14 (32%) had 2 SNPs, 4 (9% ) -1 SNP; only three (7%) individuals did not have adverse heterozygous alleles.The frequency of registration of genotypes predisposing to thromboses shown in table.At the same time, data are available on the prevalence of alleles 5G and 4G polymorphic variant of the PAI-1 gene in healthy adolescents in Russia.In particular, heterozygous genotypes of homozygotes both at the 5G allele and 4G allele are less frequently detected in patients with NOCA, and 5G / 4G are more often detected. Conclusion:The proportion of patients with NOCA among patients with ACS in 2015-2016 was 4.8%.The frequency of adverse allelic variants hemostatic gene polymorphisms associated with risk of thrombophilia in patients with ACS and NOCA was 98%.

10.1093/cvr/cvy060.118

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Identification of Protein Kinase C Isoforms in Rat Mesenteric Small Arteries and Their Possible Role in Agonist-Induced Contraction

Circulation Research (1996)

Vasken Ohanian Jacqueline Ohanian Linda Shaw Sylvia Scarth Peter J. Parker

Abstract We have identified immunologically the protein kinase C (PKC) isoforms present in rat mesenteric small arteries, defined their distribution between particulate and soluble fractions, and studied their involvement in phorbol ester–induced contraction. Our analysis revealed the presence of the Ca 2+ -dependent PKCs (α and γ), Ca 2+ -independent PKCs (δ and ε), and the atypical isoform (ζ). PKCβ could not be detected, whereas PKCγ is likely to be of neural origin. All isoforms exhibited different distributions: PKCα, PKCε, and PKCζ were found in both particulate and soluble fractions. In contrast, PKCδ was mainly in the particulate fraction, and PKCγ was in the soluble fraction. Phorbol esters, which activate PKC and cause smooth muscle contraction, downregulated only the α and δ isoforms. This was associated with a parallel loss of contractile response to phorbol ester. The force developed to submaximal concentrations of noradrenaline was decreased after phorbol dibutyrate pretreatment, although the sensitivity and maximal response were unchanged. Phorbol ester pretreatment did not affect the contractile response to vasopressin. The sensitivity to non–receptor-mediated contraction, caused by K + in the presence of prazosin, was slightly reduced by 4α- and 4β-phorbol ester pretreatment. Maximal tension in response to this agonist was not affected. We conclude that PKCα and/or PKCδ is necessary for phorbol ester–mediated contraction but is not essential for noradrenaline-, vasopressin-, or K + -induced contraction, demonstrating differences in the mechanisms involved in the contractile response between these agents.

Phorbol

Mesenteric arteries

10.1161/01.res.78.5.806

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Citations (86)

Endothelin-1 Stimulates Small Artery VCAM-1 Expression through p38MAPK-Dependent Neutral Sphingomyelinase

Journal of Vascular Research (2012)

Jacqueline Ohanian Simon P. Forman Gideon Katzenberg Vasken Ohanian

Endothelin-1 (ET-1) stimulates vascular cell adhesion molecule (VCAM-1) expression, a process associated with arterial remodelling. However, the pathways activated by ET-1 that lead to VCAM-1 expression are not fully understood. It is reported that sphingomyelinases are necessary for VCAM-1 expression in response to cytokines. Our aim was to investigate the role of sphingomyelinases in ET-1-induced VCAM-1 expression. Acid and neutral sphingomyelinase activities were measured in extracts from rat mesenteric small arteries (RMSA). ET-1 (1–100 nmol/l) stimulated neutral but not acid sphingomyelinase. The activation was rapid, peaking within 5 min and transient, returning towards baseline by 10 min and inhibited by BQ-788, GW4869 and SB203580, which are inhibitors of ET<sub>B</sub> receptor, neutral sphingomyelinase and p38MAPK, respectively. Both GW4869 and SB203580 are reported to inhibit activation of neutral sphingomyelinase 2 implicating it in the response to ET-1. Accordingly we investigated the expression of this isoform and found it was present in RMSA, predominantly in endothelial cells. Treatment of RMSA with ET-1 (1–100 nmol/l) for 16 h increased VCAM-1 expression, which was inhibited by GW4869 and SB203580. These results indicate that ET-1 stimulates arterial VCAM-1 expression through p38MAPK-dependent activation of neutral sphingomyelinases. This suggests a role for sphingolipids in ET-1-induced vascular inflammation in cardiovascular disease.

VCAM-1

Sphingomyelin phosphodiesterase

Sphingolipid

10.1159/000336649

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Citations (23)