Öz
Since the discovery of the central role of cyclooxygenase (COX) in the metabolism of arachidonic acid, vascular biologists have been exposed with the duality of this system. Essentially, one substrate (arachidonic acid) converted by one enzyme (COX) yields end products (endoperoxides) that obtain only very briefly before being metabolized to more stable prostanoids by a group of specific synthases that were primarily believed to be tissue specific. For example, thrombocytes include mainly the synthase that produces thromboxane A2 (proaggregatory and vasoconstrictor substance), though endothelial cells contain mainly the enzyme that produces prostacyclin (antiaggregatory and vasodilator substance). The overproduction of thromboxane A2 by thrombocytes induces to thrombosis. Endothelial cells lean against vascular occlusion by producing prostacyclin. This duality of the metabolism of arachidonic acid has ruled over our thinking about atherothrombosis for decades. Based on the review of these studies, we will discuss association between cyclooxygenase enzyme and endothelial dysfunction. GENEL BİLGİ Siklooksijenazlar, araşidonik asitin prostanoidlere ve diğer eikosanoidlere dönüşümünü katalizleyen enzimlerdir (1). Yapılan bilimsel çalışmalar ile birlikte siklooksijenazın COX-1 ve COX-2 adlı iki izoformunun olduğu ortaya çıkmıştır . COX-1’in başlangıçta pozitif etkili konstitütif izoform olduğu düşünülürken, COX-2’nin ağırlıklı olarak inflamatuar yanıtlarda yer alan negatif etkili bir enzim olduğu düşünülmüştür (3). Bununla birlikte, yakın zamanlarda yapılan çalışmalarla, COX-2 inhibitörlerinin yaygın kullanımından kaynaklanan kardiyovasküler hastalıklar için artmış risk bulunması ile COX-2 ürünlerinin koruyucu rol oynadıkları ve bu değerlendirilemeyeceği önerilmiştir. Benzer şekilde, araşidonik asit metabolizmasının COX-1 tarafından başlatılmasının, vasküler koruma açısından aslında çok da pozitif bir rolünün olmadığı konusunda kanıtlar ortaya çıkmıştır. Bu sonuçlar
Anahtar Kelimeler
Kaynakça
- Cipollone F, Cicolini G, Bucci M. Cyclooxygenase and prostaglandin synthases in atherosclerosis: recent insights and future perspectives. Pharmacol Ther 2008;118 (2): 161-80.
- Smith WL, Langenbach R. Why there are two 17. Feletou M, Tang EHC, Vanhoutte PM. Nitric oxide the cyclooxygenase isozymes. J Clin Invest 2001; 107(12): 149- gatekeeper of endothelial vasomotor control. Front Biosci 14
- Simmons DL, Botting RM, Hla T. Cyclooxygenase 18. Ge T, Hughes H, Junquero DC, et al. Endothelium- isozymes: the biology of prostaglandin synthesis and dependent contractions are associated with both augmented inhibition. Pharmacol Rev 2004; 56(3): 387-437.
- Félétou M, Huang Y, Vanhoutte PM. Endothelium-mediated control of vascular tone: COX-1 and COX-2 products. Br J Pharmacol. 2011; 164(3): 894-912.
- Graupera M, García-Pagán JC, Parés M, et al. receptor gene expression. J Hypertens 2002; 20: 2239-2245.
- Cyclooxygenase-1 inhibition corrects endothelial dysfunction in cirrhotic rat livers. J Hepatol 2003; 39(4): 515-21.
- Yang D, F´el´etou M, Levens N, et al. A diffusible Furchgott RF, Zawadzki JV. The obligatory role of the aorta of SHR. Hypertension 2003; 41:143-148. endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980; 288: 373-376.
- Moncada S. Nitric oxide in the vasculature: physiology and pathophysiology. Ann N Y Acad Sci 1997; 811:60-7.
- Busse R, Edwards G, Feletou M, et al. EDHF: bringing the concepts together. Trends Pharmacol Sci 2002; 23: 374-380.
- Feletou M, Vanhoutte PM. EDHF: The Complete Story. Boca Raton CRC Taylor and Francis 2006; 1-298.
- De Mey JG, Vanhoutte PM. Heterogeneous behavior of the canine arterial and venous wall. Importance of the vascular system. Trends Pharmacol Sci 2007; 28: 106-110. endothelium. Circ Res 1982; 51: 439-447.
- Therland KL, Stubbe J, Thiesson HC, et al. Cycloxygenase- Furchgott RF, Vanhoutte PM. Endothelium-derived relaxing and contracting factors. FASEB J 1989; 3: 2007-2018.
- Vanhoutte PM, Feletou M, Taddei S. Endothelium- dependent contractions in hypertension. Br J Pharmacol 2005; 144: 449-458.
- Feletou M, Vanhoutte PM. Endothelial dysfunction: a multifaceted disorder (The Wiggers Award Lecture). Am J Physiol Heart Circ Physiol 2006; 291: H985–H1002.
- Vanhoutte PM, Shimokawa H, Tang E, et al. Endothelial dysfunction and vascular disease. Acta Physiol 2009; 196:193- 2 2008;13: 4198-4217. expression of prostaglandin H synthase-1 and hypersensitivity to prostaglandin H2 in the SHR aorta. Circ Res 1995; 76:1003- 10
- Traupe T, Lang M, Goettsch W, et al. Obesity increases prostanoidmediated vasoconstriction and vascular thromboxane substance(s) mediates endothelium-dependent contractions in contractions occur in the aorta of wild-type and COX2–/– knockout but not COX1–/– knockout mice. J Cardiovasc Pharmacol 2005; 46: 761-765.
- Gluais P, Paysant J, Badier-Commander C, et al. In SHR aorta, calcium ionophore A-23187 releases prostacyclin and thromboxane A2 as endothelium-derived contracting factors.
- Am J Physiol Heart Circ Physiol 2006; 291: H2255-H2564. 2008; 586: 5295-5304.
- Smith WL, DL DeWitt, RM Garavito. Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem 2000; 69: 145-182.
- Tesfamariam B. Free radicals in diabetic endothelial cell dysfunction. Free Radic Biol Med 1994; 16: 383-391.
- De Vriese AS, Verbeuren TJ, Van de Voorde J, et al. Endothelial dysfunction in diabetes. Br J Pharmacol 2000; 130: 963-9
- Flavahan NA. Balancing prostanoid activity in the human 2 is expressed in vasculature of normal and ischemic adult human kidney and is colocalized with vascular prostaglandin E2 EP4 receptors. J Am Soc Nephrol 2004; 15(5): 1189-98.
- Taddei S, Virdis A, Mattei P, et al. Hypertension causes premature aging of endothelial function in humans. Hypertension 1997; 29: 736-743.
- Monobe H, Yamanari H, Nakamura K, et al. Effects of low-dose aspirin on endothelial function in hypertensive patients. Clin Cardiol 2001; 24: 05-709.
Öz
Siklooksijenazın (COX) araşidonik asit metabolizmasındaki büyük rolünün keşfinden beri vasküler biyologlar bu sistemin ikili fonksiyon özelliği ile karşı karşıya kalmışlardır. Gerçekten de, bir enzim (COX) tarafından dönüştürülen substrat (araşidonik asit), başlangıçta dokuya özgü olduğu inanılan bir dizi özel sentez tarafından daha kararlı prostanoidlere metabolize edilmeden önce, sadece çok kısa bir süre varolan son ürünler (endoperoksitler) üretirler. Örneğin trombositler temel olarak, tromboksan A2 (proagregan ve vazokonstriktör madde) üreten sentaz içerirlerken, endotelyal hücreler temel olarak prostasiklin (antiagregan ve vazodilatatör madde) oluşturan enzim içermektedirler. Trombositler tarafından tromboksan A2'nin aşırı üretilmesi tromboza yol açmakta; ters etki olarak da endotelyal hücrelerden prostasiklin üretilmesi vasküler tıkanmaya karşı koymaktadır. Araşidonik asit metabolizmasının bu ikili fonksiyon özelliği, yıllar boyunca aterotromboz hakkındaki düşüncelere ve çalışmalara yoğunlaşmayı sağlamıştır. Bu çalışmalardan yola çıkarak derlemede, siklooksijenaz enzimi ve endotel disfonksiyonu arasındaki ilişki tartışılacaktır.
Anahtar Kelimeler
Kaynakça
- Cipollone F, Cicolini G, Bucci M. Cyclooxygenase and prostaglandin synthases in atherosclerosis: recent insights and future perspectives. Pharmacol Ther 2008;118 (2): 161-80.
- Smith WL, Langenbach R. Why there are two 17. Feletou M, Tang EHC, Vanhoutte PM. Nitric oxide the cyclooxygenase isozymes. J Clin Invest 2001; 107(12): 149- gatekeeper of endothelial vasomotor control. Front Biosci 14
- Simmons DL, Botting RM, Hla T. Cyclooxygenase 18. Ge T, Hughes H, Junquero DC, et al. Endothelium- isozymes: the biology of prostaglandin synthesis and dependent contractions are associated with both augmented inhibition. Pharmacol Rev 2004; 56(3): 387-437.
- Félétou M, Huang Y, Vanhoutte PM. Endothelium-mediated control of vascular tone: COX-1 and COX-2 products. Br J Pharmacol. 2011; 164(3): 894-912.
- Graupera M, García-Pagán JC, Parés M, et al. receptor gene expression. J Hypertens 2002; 20: 2239-2245.
- Cyclooxygenase-1 inhibition corrects endothelial dysfunction in cirrhotic rat livers. J Hepatol 2003; 39(4): 515-21.
- Yang D, F´el´etou M, Levens N, et al. A diffusible Furchgott RF, Zawadzki JV. The obligatory role of the aorta of SHR. Hypertension 2003; 41:143-148. endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980; 288: 373-376.
- Moncada S. Nitric oxide in the vasculature: physiology and pathophysiology. Ann N Y Acad Sci 1997; 811:60-7.
- Busse R, Edwards G, Feletou M, et al. EDHF: bringing the concepts together. Trends Pharmacol Sci 2002; 23: 374-380.
- Feletou M, Vanhoutte PM. EDHF: The Complete Story. Boca Raton CRC Taylor and Francis 2006; 1-298.
- De Mey JG, Vanhoutte PM. Heterogeneous behavior of the canine arterial and venous wall. Importance of the vascular system. Trends Pharmacol Sci 2007; 28: 106-110. endothelium. Circ Res 1982; 51: 439-447.
- Therland KL, Stubbe J, Thiesson HC, et al. Cycloxygenase- Furchgott RF, Vanhoutte PM. Endothelium-derived relaxing and contracting factors. FASEB J 1989; 3: 2007-2018.
- Vanhoutte PM, Feletou M, Taddei S. Endothelium- dependent contractions in hypertension. Br J Pharmacol 2005; 144: 449-458.
- Feletou M, Vanhoutte PM. Endothelial dysfunction: a multifaceted disorder (The Wiggers Award Lecture). Am J Physiol Heart Circ Physiol 2006; 291: H985–H1002.
- Vanhoutte PM, Shimokawa H, Tang E, et al. Endothelial dysfunction and vascular disease. Acta Physiol 2009; 196:193- 2 2008;13: 4198-4217. expression of prostaglandin H synthase-1 and hypersensitivity to prostaglandin H2 in the SHR aorta. Circ Res 1995; 76:1003- 10
- Traupe T, Lang M, Goettsch W, et al. Obesity increases prostanoidmediated vasoconstriction and vascular thromboxane substance(s) mediates endothelium-dependent contractions in contractions occur in the aorta of wild-type and COX2–/– knockout but not COX1–/– knockout mice. J Cardiovasc Pharmacol 2005; 46: 761-765.
- Gluais P, Paysant J, Badier-Commander C, et al. In SHR aorta, calcium ionophore A-23187 releases prostacyclin and thromboxane A2 as endothelium-derived contracting factors.
- Am J Physiol Heart Circ Physiol 2006; 291: H2255-H2564. 2008; 586: 5295-5304.
- Smith WL, DL DeWitt, RM Garavito. Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem 2000; 69: 145-182.
- Tesfamariam B. Free radicals in diabetic endothelial cell dysfunction. Free Radic Biol Med 1994; 16: 383-391.
- De Vriese AS, Verbeuren TJ, Van de Voorde J, et al. Endothelial dysfunction in diabetes. Br J Pharmacol 2000; 130: 963-9
- Flavahan NA. Balancing prostanoid activity in the human 2 is expressed in vasculature of normal and ischemic adult human kidney and is colocalized with vascular prostaglandin E2 EP4 receptors. J Am Soc Nephrol 2004; 15(5): 1189-98.
- Taddei S, Virdis A, Mattei P, et al. Hypertension causes premature aging of endothelial function in humans. Hypertension 1997; 29: 736-743.
- Monobe H, Yamanari H, Nakamura K, et al. Effects of low-dose aspirin on endothelial function in hypertensive patients. Clin Cardiol 2001; 24: 05-709.
Ayrıntılar
| Birincil Dil | Türkçe |
|---|---|
| Bölüm | Makale |
| Yazarlar | |
| Yayımlanma Tarihi | 28 Ekim 2013 |
| Yayımlandığı Sayı | Yıl 2013 Cilt: 3 Sayı: 5 |
