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Targeting eNOS for stroke protection

Targeting eNOS for stroke protection. Li-ping Wu 2004-10-13. Background. L-arginine. nitric oxide synthase (NOS). eNOS. NO. In vascular diseases. Neuroprotective:increasing cerebral Blood flow during brain ischemia Vasodilatory Anti-inflammatory Antithrombotic

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Targeting eNOS for stroke protection

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  1. Targeting eNOS for stroke protection Li-ping Wu 2004-10-13

  2. Background L-arginine nitric oxide synthase(NOS) eNOS NO In vascular diseases • Neuroprotective:increasing cerebral Blood flow during brain ischemia • Vasodilatory • Anti-inflammatory • Antithrombotic • Antiproliferative

  3. 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

  4. eNOS: neuroprotective eNOS (knocked out) regional cerebral blood flow cerebral infarction nNOS

  5. eNOS: neuroprotective L-NAME (inhibiting activity) eNOS regional cerebral blood flow cerebral infarction nNOS (lacking)

  6. eNOS: neuroprotective (enhancing NO production) eNOS regional cerebral blood flow L-arginine cerebral infarction nNOS

  7. eNOS: neuroprotective Enhanacing eNOS function Increase the number of circulating Endothelial Progenitor cells (EPCs) Contribute to neovasularization after ischemia stroke

  8. Janus effect of NO in the brain brain ischemia eNOS iNOS nNOS NO toxic to surrounding neurons neuroprotective secondary damage

  9. What we should do ? eNOS upregulate and/or activate how nNOS inhibit iNOS

  10. How to upregulate/activate eNOS Statins Steroid hormones Physical activity Nutrients

  11. Statins Statins: cholesterol lowering inhibitors of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase

  12. 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

  13. Steroid hormones corticosteroids oestrogen Directly activate eNOS

  14. corticosteroids GR corticosteroids Mechanism: Transcriptional effect: modulation of target genes by glucocorticoid receptor (GR) Non-nuclear effect: eNOS activation PI3K and PKB/Akt NO bioavailability

  15. 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)

  16. eNOS activity 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

  17. oestrogen Strongly neuroprotective effect in animal models of stroke No effect in clinical trials of primary prevention

  18. Physical activity Regular physical activity • Mechanism: • relating to alterations in blood flow • increasing the number of circulating EPCs • increasing neovascularization

  19. Nutrients Red wine and diets rich in flavonoids and plant polyphenols Mechanism: ?

  20. eNOS uncoupling Uncoupling of eNOS L-arginine enhancing ROS production eNOS superoxide NO BH4 NADPH oxidase Vascular damage

  21. 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)

  22. 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

  23. Concluding remarks Althoughseveral important caveats, such as eNOS uncoupling and the dual role of NO in brain ischemia have to be considered Howeverstatins, physical activity, steroid hormones and nutrients can Lead to eNOS upregulation or activation, which protects from brain ischemic stroke ThuseNOS targeting is an attractive approach to prevent and treat stroke in humans

  24. Thank you

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