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Targeting eNOS for stroke protection
Li-ping Wu 2004-10-13
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Background
L-arginine
nitric oxide synthase (NOS)
eNOS
NO
In vascular diseases

• Neuroprotectiveincreasing cerebral Blood
• flow during brain ischemia
• Vasodilatory
• Anti-inflammatory
• Antithrombotic
• Antiproliferative

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Main isomers of NOS

• Constitutively expressed
• Calcium-dependent
• Including

cNOS consitutive form
Neuronal (nNOS)
Endothelial (eNOS)
iNOS inducible form

• Induced in inflammatory and other cell types by
• stimuli such as endotoxin and
  proinflammatory
• cytokines
• Calcium-independent

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eNOS neuroprotective
eNOS
(knocked out)
regional cerebral blood flow
cerebral infarction
nNOS
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eNOS neuroprotective
L-NAME
(inhibiting activity)
eNOS
regional cerebral blood flow
cerebral infarction
nNOS
(lacking)
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(enhancing NO production)
eNOS
regional cerebral blood flow
L-arginine
cerebral infarction
nNOS
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Enhanacing eNOS function
Increase the number of circulating Endothelial
Progenitor cells (EPCs)
Contribute to neovasularization after ischemia
stroke
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Janus effect of NO in the brain
brain ischemia
iNOS
eNOS
nNOS
NO
toxic to surrounding neurons
secondary damage
neuroprotective
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What we should do
?
eNOS
upregulate and/or activate
how
nNOS
inhibit
iNOS
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How to upregulate/activate eNOS
Statins
Steroid hormones
Physical activity
Nutrients
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Statins
Statins cholesterol lowering
inhibitors of hydroxymethylglutaryl
coenzyme A (HMG-CoA) reductase
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Statins
Mechanism

• Indirectly by reducing cholesterol
  levels

• Directly by stability of eNOS mRNA
• by activating the
  pathway involving
• phosphoinositide
  3-kinase (PI3K)
• and PKB/Akt

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Steroid hormones
corticosteroids
oestrogen
Directly activate eNOS
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corticosteroids
Mechanism
Transcriptional effect modulation of target
genes by
glucocorticoid receptor (GR)
Non-nuclear effect eNOS activation
PI3K and PKB/Akt
NO bioavailability
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corticosteroids
In animal models
Depending on the dose and duration
of corticosteroid administration
In clinical practice
not good
Ten times higher dose
Hyperglycemia (lactate acidosis)
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oestrogen
Mechanism
Genomic effects an interaction between oestrogen
receptor and
regulatory subunit of PI3K
Nontranscriptional effects direct binding of the
oestrogen receptor a
isoform to PI3K
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oestrogen
Strongly neuroprotective effect in animal models
of stroke
No effect in clinical trials of primary prevention
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Physical activity
Regular physical activity

• Mechanism
• relating to alterations in blood flow
• increasing the number of circulating EPCs
• increasing neovascularization

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Nutrients
Red wine and diets rich in flavonoids and plant
polyphenols
Mechanism ?
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Uncoupling of eNOS
L-arginine
enhancing ROS production
eNOS
superoxide
NO
BH4
NADPH oxidase
Vascular damage
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eNOS protect against stroke in human?
preventive approaches
chronic eNOS upregulation

• regular physical activity

primary and secondary prevention

• moderate consumption of red wine

• chronic statin treatment

high risk patients (high dose)
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eNOS protect against stroke in human?
acute approaches
eNOS activation

• PI3K-Akt-mediated eNOS activation can be achieved
  administration
• of statins,corticosteroids and oestrogens

• L-arginine could be directly administered
  intravenously to increase
• NO production

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Concluding remarks
Although several important caveats, such as
eNOS uncoupling and the dual role of NO in brain
ischemia have to be considered However
statins, physical activity, steroid hormones and
nutrients can Lead to eNOS upregulation or
activation, which protects from brain ischemic
stroke Thus eNOS targeting is an attractive
approach to prevent and treat stroke in humans
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Thank
you