Conclusions

Oxidized lipid mediators generated by PGHS, LOX, or CYP are of central importance in the normal physiology of the endothelium, with their aberrant generation playing a major role in the pathogenesis of inflammatory vascular disease. In addition, these enzymes generate a small amount of lipid radicals that may propagate nonenzymatic lipid peroxidation, a hallmark of atherosclerotic lesions. Although much is known regarding function and control of these pathways in ECs (especially PGHS and LOX), others, especially the CYP enzymes, are less studied. Studying the biological roles and signaling pathways of CYP in EC is becoming a major focus of research in vascular biology and will undoubtedly lead to a fuller understanding of their roles in both normal homeostasis and vascular pathophysiology.

Finally, although much is known regarding the biological chemistry and cell biology of these pathways, their relative importance in vessels of different origin is not clear. In particular, the role of PGHS, LOX, or CYP in control of vascular tone through regulating vascular function in large vessels, resistance vessels, and capillary beds may vary tremendously. Elucidation of tissue-specific functions and control mechanisms for lipid oxidation pathways in subtypes of EC is becoming an area of active and fruitful investigation that will yield major insights into their role in regulating vascular biology in health and disease.

Glossary

Lipoxygenases: Lipid oxidizing enzymes that play important roles in vascular function and immune regulation. There are several mammalian isoforms, with one in particular (12/15-lipoxygenase) being involved in vascular dysfunction associated with hypertension, diabetes, and atherogenesis.

Nitric oxide: Free radical signaling molecule generated by oxidation of L-arginine by nitric oxide synthases (NOS), which causes smooth muscle relaxation and inhibits platelet and leukocyte activation.

Prostaglandin H synthases: Lipid oxidizing enzymes that generate prostaglandins, signaling mediators that regulate vessel tone (e.g., prosta-cyclin) and platelet aggregation (e.g., thromboxane).

Acknowledgments

Research funding from the Wellcome Trust and British Heart Foundation is gratefully acknowledged.

Bibliography

Prostaglandin H Synthase

Belton, O., Byrne, D., Kearney, D., Leahy, A., and Fitzgerald, D. J. (2000). Cyclooxygenase-1 and -2-dependent prostacyclin formation in patients with atherosclerosis Circulation 102, 840-845. This study describes the relative importance of PGHS-1 and -2 in generation of prostanoids in vivo in humans with vascular disease. Caughey, G. E., Cleland, L. G., Penglis, P. S., Gamble, J. R., and James, M. J. (2001). Roles of cyclooxygenase (COX)-1 and COX-2 in prostanoid production by human endothelial cells: Selective up-regulation of prostacyclin synthesis by COX-2. J. Immunol. 167, 2831-2838.

Smith, W. L., and Marnett, L. J. (1991). Prostaglandin endoperoxide synthase: Structure and catalysis. Biochim. Biophys. Acta 1083, 1-17. This is an excellent review on PGHS isoforms, focusing mainly on the biochemistry and enzymology of these pathways.

Lipoxygenases

Feinmark, S. J., and Cannon, P. J. (1986). Endothelial cell leukotriene C4 synthesis results from intercellular transfer of leukotriene A4 synthe-sised by polymorphonuclear leukocytes. J. Biol. Chem. 261, 16466-16472.

Kühn, H., Belkner, J., Zaiss, S., Fahrenklemper, T., and Wohlfeil, S. (1994). Involvement of 15-lipoxygenase in early stages of atherogenesis. J. Exp. Med. 179, 1903-1911.

Liu, B., Marnett, L. J., Chaudhary, A., Ji, C., Blair, I. A., Johnson, C. R., Diglio, C. A., and Honn, K. V. (1994). Biosynthesis of 12(S)hydroxye-icosatetraenoic acid by B16 amelanotic melanoma cells is a determinant of their metastatic potential. Lab. Invest. 70, 314.

Zhang, Y. Y., Walker, J. L., Huang, A., Keaney, J. F., Clish, C. B., Serhan, C. N., and Loscalzo, J. (2002). Expression of 5-lipoxygenase in pulmonary artery endothelial cells. Biochem. J. 361, 267-276.

Cytochrome P450

Campbell, W. B., Gebremedhin, S., Pratt, P. F., and Harder, D. R. (1996). Identification of epoxyeicosatrienoic acids as endothelium-derived hyperpolarizing factors. Circ. Res. 78, 415-423.

Capdevila, J. H., Falck, J. R., and Estabrook, R. W. (1992). Cytochrome P450 and the arachidonate cascade. FASEB J. 6, 731-736. This is an excellent review on the enzymology of CYP oxidation of arachidonate to bioactive mediators. Although it maybe a little out-of-date, it still is a very useful starting point for the reader new to the area.

Rosolowski, M., and Campbell, W. B. (1996). Synthesis of hydroxye-icosatetraenoic (HETEs) and epoxyeicosatrienoic acids (EETs) by cultured bovine artery endothelial cells. Biochim. Biophys. Acta 1299, 267-277.

Capsule Biography

Drs. Anning and O'Donnell are based at Cardiff University, UK. Their work focuses on lipoxygenase and nitric oxide signaling in the vasculature and is funded by the British Heart Foundation and Wellcome Trust.

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