L53	Epoxyeicosatrienoic acids in vascular homeostasis.
I.Fleming
Johann Wolfgang Goethe Universität, Frankfurt/Main, DE.

Nitric oxide and prostacyclin-independent vasodilatation in several vascular beds has been linked to the activation of cytochrome P450 (CYP) epoxygenases expressed in endothelial cells and the generation of vasodilator epoxyeicosatrienoic acids (EETs). EETs contribute to the activation of Ca2+-dependent K+ channels in endothelial cells and the subsequent hyperpolarization, by a mechanism that involves the opening of TRP channels and an increase in transmembraneous Ca2+ influx. Moreover, EETs potentiate inter-endothelial gap junctional communication by a cyclic AMP/protein kinase A-dependent process, and thus contribute to the phenomenon of ascending dilation. EETs are not only involved in the regulation of vascular tone since they also modulate the activity of protein tyrosine phosphatases and activate several intracellular protein kinases including tyrosine kinases, the p38 MAP kinase, ERK1/2, as well as Akt/PKB. Overexpression of CYP 2C9 in cultured human endothelial cells also markedly increases proliferation and stimulates both cell migration and angiogenesis, effects that can, at least partially, be attributed to the transactivation of the EGF receptor. CYP enzymes may also produce oxygen-derived free radicals which attenuate the bioavailability of NO. In patients with manifest coronary artery disease and pronounced endothelial dysfunction the CYP 2C9 inhibitor, sulfaphenazole, enhances endothelium-dependent vasodilator responses. This effect appears to be related to an increase in the bioavailability of NO, most probably as a consequence of an attenuated generation of reactive oxygen species by CYP 2C9 in endothelial cells. The reason for the switch from vasodilator EET to O2- production remains to be determined but may be linked to an increase in CYP 2C expression and/or an alteration in the substrate metabolised by the enzyme.

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