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Investigation into the intracellular mechanisms whereby long-chain fatty acids protect the heart in ischaemia/reperfusionEngelbrecht, Anna-Mart 03 1900 (has links)
Thessis (PhD)--Stellenbosch University, 2005. / ENGLISH ABSTRACT: Although there is evidence for a protective role of long-chain polyunsaturated
fatty acids (PUFAs) in cardiovascular disease, their mechanism of action as
well as their participation in intracellular signalling processes remain to be
elucidated. Therefore the aims of this study were twofold: (i) to characterize
the roles of the mitogen-activated protein kinases (MAPKs) and protein kinase
B (PKB/Akt) in ischaemia/reperfusion-induced apoptosis of neonatal
cardiomyocytes and (ii) to establish whether long-chain PUFAs protect the
heart via manipulation of these kinases.
Rat neonatal ventricular myocytes exposed to simulated ischaemia and
reperfusion (Sl/R) were used to characterize the role(s) of extracellular signalregulated
kinase (ERK), p38 and c-Jun NH2-terminal protein kinase (JNK), as
well as PKB/Akt in apoptosis. The effects of an omega-3 fatty acid
(eicosapentaenoic acid - EPA) and an omega-6 fatty acid (arachidonic acid -
ARA) on the response of neonatal rat cardiomyocytes to Sl/R with regard to
the above parameters were determined.
Exposure of the myocytes to SI (energy depletion induced by KCN and 2-
deoxy-D-glucose) reduced cell viability, as measured by the 3-[4,5-
dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay, and
stimulated apoptosis (increased caspase-3 activation and poly(ADP-ribose)
polymerase (PARP) cleavage). However, morphological evidence of
increased apoptosis (Hoechst 33342 staining) occurred only after reperfusion.
A rapid activation of p38 and PKB/Akt Ser473 occurred during SI, while
significant activation of ERK and JNK was observed during reperfusion only.
Myocytes pre-treated with SB203580, a p38-inhibitor, displayed a significant
increase in cell viability and attenuation of apoptosis during Sl/R, while
SP600125, a specific JNK inhibitor, significantly increased both caspase-3
activation and the apoptotic index. However, PD98059, an ERK inhibitor, was
without effect. Wortmannin, a PI3-kinase inhibitor, reduced PKB/Akt Thr308 but
not Ser473 phosphorylation during Sl/R and caused a significant increase in Although there is evidence for a protective role of long-chain polyunsaturated
fatty acids (PUFAs) in cardiovascular disease, their mechanism of action as
well as their participation in intracellular signalling processes remain to be
elucidated. Therefore the aims of this study were twofold: (i) to characterize
the roles of the mitogen-activated protein kinases (MAPKs) and protein kinase
B (PKB/Akt) in ischaemia/reperfusion-induced apoptosis of neonatal
cardiomyocytes and (ii) to establish whether long-chain PUFAs protect the
heart via manipulation of these kinases.
Rat neonatal ventricular myocytes exposed to simulated ischaemia and
reperfusion (Sl/R) were used to characterize the role(s) of extracellular signalregulated
kinase (ERK), p38 and c-Jun NH2-terminal protein kinase (JNK), as
well as PKB/Akt in apoptosis. The effects of an omega-3 fatty acid
(eicosapentaenoic acid - EPA) and an omega-6 fatty acid (arachidonic acid -
ARA) on the response of neonatal rat cardiomyocytes to Sl/R with regard to
the above parameters were determined.
Exposure of the myocytes to SI (energy depletion induced by KCN and 2-
deoxy-D-glucose) reduced cell viability, as measured by the 3-[4,5-
dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay, and
stimulated apoptosis (increased caspase-3 activation and poly(ADP-ribose)
polymerase (PARP) cleavage). However, morphological evidence of
increased apoptosis (Hoechst 33342 staining) occurred only after reperfusion.
A rapid activation of p38 and PKB/Akt Ser473 occurred during SI, while
significant activation of ERK and JNK was observed during reperfusion only.
Myocytes pre-treated with SB203580, a p38-inhibitor, displayed a significant
increase in cell viability and attenuation of apoptosis during Sl/R, while
SP600125, a specific JNK inhibitor, significantly increased both caspase-3
activation and the apoptotic index. However, PD98059, an ERK inhibitor, was
without effect. Wortmannin, a PI3-kinase inhibitor, reduced PKB/Akt Thr308 but
not Ser473 phosphorylation during Sl/R and caused a significant increase in Although there is evidence for a protective role of long-chain polyunsaturated
fatty acids (PUFAs) in cardiovascular disease, their mechanism of action as
well as their participation in intracellular signalling processes remain to be
elucidated. Therefore the aims of this study were twofold: (i) to characterize
the roles of the mitogen-activated protein kinases (MAPKs) and protein kinase
B (PKB/Akt) in ischaemia/reperfusion-induced apoptosis of neonatal
cardiomyocytes and (ii) to establish whether long-chain PUFAs protect the
heart via manipulation of these kinases.
Rat neonatal ventricular myocytes exposed to simulated ischaemia and
reperfusion (Sl/R) were used to characterize the role(s) of extracellular signalregulated
kinase (ERK), p38 and c-Jun NH2-terminal protein kinase (JNK), as
well as PKB/Akt in apoptosis. The effects of an omega-3 fatty acid
(eicosapentaenoic acid - EPA) and an omega-6 fatty acid (arachidonic acid -
ARA) on the response of neonatal rat cardiomyocytes to Sl/R with regard to
the above parameters were determined.
Exposure of the myocytes to SI (energy depletion induced by KCN and 2-
deoxy-D-glucose) reduced cell viability, as measured by the 3-[4,5-
dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay, and
stimulated apoptosis (increased caspase-3 activation and poly(ADP-ribose)
polymerase (PARP) cleavage). However, morphological evidence of
increased apoptosis (Hoechst 33342 staining) occurred only after reperfusion.
A rapid activation of p38 and PKB/Akt Ser473 occurred during SI, while
significant activation of ERK and JNK was observed during reperfusion only.
Myocytes pre-treated with SB203580, a p38-inhibitor, displayed a significant
increase in cell viability and attenuation of apoptosis during Sl/R, while
SP600125, a specific JNK inhibitor, significantly increased both caspase-3
activation and the apoptotic index. However, PD98059, an ERK inhibitor, was
without effect. Wortmannin, a PI3-kinase inhibitor, reduced PKB/Akt Thr308 but
not Ser473 phosphorylation during Sl/R and caused a significant increase in PARP cleavage during reperfusion, but had no effect on caspase-3 activation
or the apoptotic index.
EPA and ARA (20 jiM, present before and after SI) significantly reduced
caspase-3 activation, PARP-cleavage and the apoptotic index during
reperfusion. This was associated with increased ERK- and decreased p38
phosphorylation. Vanadate (a tyrosine phosphatase inhibitor), but not okadaic
acid (a serine-threonine phosphatase inhibitor), significantly reduced ARAinduced
inhibition of p38 phosphorylation, suggesting involvement of tyrosine
phosphatases during Sl/R. MKP-1, a dual-specificity phosphatase, was
targeted and a significant induction of MKP-1 by ARA and EPA was observed.
An in vitro dephosphorylation assay confirmed that this phosphatase might be
responsible for the inhibition of p38 activation. It was also demonstrated that
the protective actions of ARA are PI3-K dependent.
The results suggest that p38 has a pro-apoptotic role while JNK
phosphorylation is protective and that these kinases act via caspase-3 to
prevent or promote cell survival in response to SI/R-induced injury. It was
demonstrated for the first time that EPA and ARA protect neonatal cardiac
myocytes from ischaemia/reperfusion-induced apoptosis through induction of
a dual-specific phosphatase, MKP-1, causing dephosphorylation of the proapoptotic
kinase, p38. These beneficial effects of ARA and EPA were also
reflected by improvement in functional recovery during ischaemia/reperfusion
of the isolated perfused rat heart model. / AFRIKAANSE OPSOMMING: Dit word algemeen aanvaar dat lang-ketting poli-onversadigde vetsure teen
kardiovaskulere siektes beskerm, maar hul meganisme van aksie sowel as
hul invloed op intrasellulere seinoordragpaaie is egter onbekend. Die
doelwitte van hierdie studie is dus tweevoudig: (i) om die belang van
mitogeen-geaktiveerde proteien kinases (MAPKs) en protein kinase B
(PKB/Akt) in isgemie/herperfusie-geinduseerde apoptose vas te stel en (ii) om
te bepaal of lang-ketting poli-onversadigde vetsure die hart, deur manipulering
van hierdie kinases, beskerm.
Rot neonatale ventrikulere miosiete, blootgestel aan gesimuleerde isgemie en
herperfusie (Sl/H), is gebruik om die aktivering van ekstrasellulere seingereguleerde
kinase (ERK), p38, c-Jun NH2-terminale protein kinase (JNK)
asook PKB/Akt tydens apoptose, te karakteriseer. Die effek van ‘n omega-3
vetsuur (eikosapentaenoSsuur - EPA) en ‘n omega-6 vetsuur (aragidoonsuur
- ARA) op die respons van bogenoemde kinases in neonatale kardiomiosiete
tydens Sl/H, is ondersoek.
Blootstelling van miosiete aan SI (energie-uitputting gemduseer deur
kaliumsianied en 2-deoksi-D-glukose) het ‘n afname in die vermoe van die sel
om te oorleef, soos gemeet deur die MTT (3-[4,5-dimetieltiazol-2-yl]-2,5-
difeniel tetrazolium bromied) bepaling, tot gevolg gehad. ‘n Toename in
apoptose (kaspase-3 aktivering en poli(ADP-ribose) polimerase (PARP)
kliewing) is ook waargeneem. Morfologiese bewyse van apoptose (Hoechst
33342 kleuring) was egter eers tydens herperfusie sigbaar. SI is gekenmerk
deur vinnige aktivering van p38 en PKB/Akt Ser473, terwyl ERK en JNK
fosforilering slegs tydens herperfusie waargeneem is. Vooraf-behandeling met
SB203580, ‘n p38 inhibitor, het ‘n beduidende toename in
sellewensvatbaarheid asook ‘n afname in die apoptotiese indeks tydens Sl/H
teweeggebring, terwyl SP600125, ‘n spesifieke JNK inhibitor, apoptose
bevorder het. PD98059, ‘n ERK inhibitor, het geen invloed op apoptose
tydens Sl/H gehad nie. Wortmannin, ‘n PI3-kinase inhibitor, het Thr308 (nie
Ser473) fosforilering onderdruk, gepaargaande met ‘n toename in PARP kliewing, maar dit het geen invloed op kaspase-3 aktivering of die apoptotiese
indeks gehad nie.
EPA en ARA (20 (iM, teenwoordig voor en na SI) het kaspase-3 aktivering en
PARP kliewing asook die apoptotiese indeks tydens herperfusie beduidend
verminder. Beide vetsure het ook ‘n beduidende toename in ERK en afname
in p38 fosforilering veroorsaak. Vanadaat (‘n serien-threonien fosfatase
inhibitor), maar nie “okadaic” suur (‘n tirosien fosfatase inhibitor), kon die
ARA-gemduseerde inhibisie van p38 ophef nie. Induksie van MKP-1, ‘n
tweeledige-spesifieke fosfatase, is beduidend deur ARA en EPA tydens
herperfusie verhoog. 'n In vitro defosforileringbepaling het bevestig dat hierdie
fosfatase wel betrokke by die inhibisie van p38 kan wees. Daarbenewens is
gevind dat die beskermende aksie van ARA PI3-K afhanklik is.
Hierdie resultate wys dat fosforilering van p38 pro-apoptoties is, terwyl JNK
beskermend is en dat hierdie kinases via kaspase-3 seldood of oorlewing
tydens SI/H-geinduseerde beskadiging bemiddel. In hierdie model is daar vir
die eerste keer getoon dat EPA en ARA neonatale kardiale miosiete teen
isgemie/herperfusie-geinduseerde apoptose beskerm deur induksie van MKP-
1, wat defosforilering van die pro-apoptotiese kinase, p38 teweegbring.
Hierdie voordelige effekte van EPA en ARA is ook sigbaar in die funksionele
herstel tydens isgemie/herperfusie van die geisoleerde rothart model.
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Management of adverse gastrointestinal events in patients with anti-platelet therapyNg, Fook-hong., 吳福康. January 2008 (has links)
published_or_final_version / Medicine / Master / Doctor of Medicine
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103 |
Utility of cardiac biomarkers in end-stage renal disease patients on maintenance peritoneal dialysisWang, Yee-moon, Angela., 王依滿. January 2008 (has links)
published_or_final_version / Medicine / Doctoral / Doctor of Philosophy
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104 |
Polyol pathway contributes to hyperglycemia-induced cardiac dysfunctionCheng, Wing-tim., 鄭永添. January 2008 (has links)
published_or_final_version / Physiology / Master / Master of Philosophy
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105 |
APPL1 as a novel signaling mediator of adiponectin and insulin: molecular mechanisms and physiologicalimplicationsCheng, King-yip, 鄭競業 January 2009 (has links)
published_or_final_version / Medicine / Doctoral / Doctor of Philosophy
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106 |
Relationship between psychological status and vascular function in subjects with and without cardiovascular diseasesChen, Hua, 陳華 January 2008 (has links)
published_or_final_version / Medicine / Master / Master of Philosophy
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107 |
A study on the perceptions and behaviour on smoking cessation among patients with cardiovascular disease (CVD) hospitalized in a smoke-free hospital in Beijing, ChinaZhang, Jingyu, 张京煜 January 2009 (has links)
published_or_final_version / Nursing Studies / Master / Master of Philosophy
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The effect of supplementation with n-9, n-6, and n-3 fatty acids on plasma lipid, lipoprotein, apolipoprotein B concentrations, LDL particle size, and oxidative susceptibility of two LDL subfractions in postmenopausal womenLee, Ye-Sun 21 September 1999 (has links)
Current dietary recommendations have placed increasing emphasis on dietary fat
as an important element to decrease risk of cardiovascular disease (CVD). Although total
fat and the fatty acid composition of diets influence the risk of CVD, the optimal amounts
of different fatty acids are not well defined, especially if n-6 and n-3 fatty acids are
considered. Despite the fact that postmenopausal women are at increased risk of CVD,
few studies have investigated the influence of dietary fatty acids on this risk. Therefore,
this study was designed to determine the effect of supplementation with different fatty
acids on risk factors of CVD in postmenopausal women. Sixteen healthy,
postmenopausal women were randomly assigned in a three-period crossover trial to
treatments of 15 g/d supplements of oleic acid-rich sunflower oil (TS), linoleic acid-rich safflower oil (SO), and eicosapentaenoic acid- and docosahexaenoic acid-rich fish oil
(FO). Each treatment period lasted 5 weeks followed by a 7-week washout interval.
When the women were supplemented with FO compared to supplementation with either
TS or SO, the concentration of high density lipoprotein cholesterol tended to increase
(p=0.07 and 0.05, respectively) as did the size of the low density lipoprotein (LDL)
particle (P=0.03 in both instances) while the concentration of triacylglycerol (p=0.0001
and 0.02, respectively) and apolipoprotein B (apo B) (P=0.005 and P=0.01, respectively)
decreased. The concentration , i.e., total cholesterol, cholesterol ester, free cholesterol,
phospholipids, α- and γ-tocopherol, of the two LDL subfractions was not influenced by
any of the oil supplements but was greater in the large (L) subfraction than the small (S).
When the oxidation of the two subfractions was measured by monitoring the formation of
conjugated dienes, the lag time was shorter in both fractions after supplementation with
FO compared to supplementation with SO (P=0.0001) or TS (P=0.0001) but the effect
was greater in the L subfraction. The rate of formation of conjugated dienes, which was
slower after FO supplementation than supplementation with either TS (P=0.02) or SO
(P=0.001), was faster in the L compared to the S subfraction. When oxidation was
measured by monitoring the increase in negative charge on apo B over 23 hr, only the 1
hr time point differed. The increase was greater in the FO-supplemented
group than either the TS- or SO-supplemented groups (P=0.001 in both instances). The
change was greater in S LDL (P=0.007). These findings demonstrate a greater potential
antiatherogenic property of dietary n-3-rich oil than n-6- or n-9-rich ones as indicated by
changes to plasma lipids, lipoproteins, apo B, and particle size but the influence of the
oxidative susceptibility of L and S subfractions is less conclusive. / Graduation date: 2000
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THE EFFECT OF BETA ADRENERGIC BLOCKADE ON RATINGS OF PERCEIVED EXERTION.Hartzell, Albert Anthony. January 1984 (has links)
No description available.
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THE EFFECTS OF CARDIOSELECTIVE AND NON-SELECTIVE BETA ADRENERGIC BLOCKADE ON THE PERFORMANCE OF HIGHLY TRAINED RUNNERS.Anderson, Richard Lloyd. January 1984 (has links)
No description available.
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