FLUVASTATİNİN TAVŞAN KAROTİD ARTERİ YAKA MODELİNDE İNTİMAL KALINLAŞMA ÜZERİNE ETKİLERİ

Yıl 2018, , 144 - 147, 04.04.2018

Mehmet Zuhuri Arun , Gülnur Sevin Şule Ayla , Gülperi Öktem , Günay Yetik Anacak Levent Üstünes

https://doi.org/10.16948/zktipb.397803

Öz

Amaç: Statinlerin
LDL-kolesterol düşürücü etkilerinden bağımsız endotel fonksiyonu gibi aterosklerozun
pek çok bileşeni üzerinde de etkileri mevcuttur. Bu etkileri pleiotropik
etkileri olarak da bilinmektedir. Bu çalışmada fluvastatinin normokolesterolemik
tavşanlarda intimal kalınlaşma üzerine etkisinin araştırılması planlanmıştır.

Gereç ve Yöntem: Çalışmada Yeni Zelanda tavşanlarına 3 hafta boyunca
fluvastatin (8 mg/kg/gün oral) ve plasebo tedavi uygulandı. Tedavinin sekizinci
gününde okluzif olmayan silikon bir yaka sol karotid arterinin çevresine
yerleştirilerek on dört gün daha tedaviye devam edildi. Deney sonunda sağ ve
sol karotid arterler çıkarıldı. Çıkarılan karotid arterlerden alınan kesitlerde
morfometrik ölçümler gerçekleştirildi. İntima, medya, lümen ve eksternal
elastik lamina alanları ölçülerek indeks, rezidüel lümen oranı değerleri
hesaplandı.

Bulgular: Yaka intimal
alan ve indeks değerinde belirgin bir artışa ve RLO değerinde azalmaya neden
olurken fluvastatin yakanın neden olduğu intimal kalınlaşmayı inhibe etti.

Sonuç: Bulgularımız
fluvastatinin kolesterol düşürücü etkisinden bağımsız aterosklerozun erken
döneminde de yararlı etkileri olabileceğini göstermektedir.

Anahtar Kelimeler

fluvastatin, statin, intimal kalınlaşma, yaka modeli, karotid arteri

Effects of fluvastatin on intimal thickening in rabbit carotid artery collar model

Öz

Objective: Statins may
exert effects that are independent of LDL-cholesterol lowering on many
components of atherosclerosis including endothelial function, called
pleiotropic effects. In this study we aimed to investigate effects of
fluvastatin on intimal thickening in normocholesterolemic rabbits.

Materials &Method: New Zeeland
rabbits were treated with fluvastatin (8 mg/kg/day, p.o.) and placebo for 3
weeks. On the 8th day, a non-occlusive silicon collar was positioned around the
left carotid artery for 14 days and then both carotid arteries were isolated.
Intimal, medial, lumen and external elastic lamina cross sectional areas were
measured by computer based morphometric analysis and index (intima/media),
residual luminal ratio (RLR) values were calculated.

Results: Collar
caused significant increase in intimal area, index values and decrease in RLR
values. Fluvastatin treatment significantly inhibit collar-induced intimal
thickening.

Conclusion: These
findings indicate that fluvastatin may have beneficial effects on the early
stages of normocholesterolemic atherosclerosis.

Anahtar Kelimeler

fluvastatin, statins, intimal thickening, collar, carotid artery

Kaynakça

• Herrington, W., et al., Epidemiology of Atherosclerosis and the Potential to Reduce the Global Burden of Atherothrombotic Disease. Circ Res, 2016. 118(4): p. 535-46.
• Davies, M.G. and P.O. Hagen, Pathobiology of intimal hyperplasia. Br J Surg, 1994. 81(9): p. 1254-69.
• Booth, R.F., et al., Rapid development of atherosclerotic lesions in the rabbit carotid artery induced by perivascular manipulation. Atherosclerosis, 1989. 76(2-3): p. 257-68.
• Oesterle, A., U. Laufs, and J.K. Liao, Pleiotropic Effects of Statins on the Cardiovascular System. Circulation research, 2017. 120(1): p. 229-243.
• Schneider, J.E., et al., Probucol decreases neointimal formation in a swine model of coronary artery balloon injury. A possible role for antioxidants in restenosis. Circulation, 1993. 88(2): p. 628-637.
• Arun, M.Z., et al., Effects of vitamin C treatment on collar-induced intimal thickening. Drug Des Devel Ther, 2015. 9: p. 6461-73.
• Ustunes, L., et al., Effect of verapamil on intimal thickening and vascular reactivity in the collared carotid artery of the rabbit. Br J Pharmacol, 1996. 118(7): p. 1681-8.
• Van Put, D.J., et al., Dexamethasone influences intimal thickening and vascular reactivity in the rabbit collared carotid artery. Eur J Pharmacol, 1995. 294(2-3): p. 753-61.
• Renna, N.F., N. de Las Heras, and R.M. Miatello, Pathophysiology of vascular remodeling in hypertension. Int J Hypertens, 2013. 2013: p. 808353.
• Libby, P. and M. Aikawa, Effects of statins in reducing thrombotic risk and modulating plaque vulnerability. Clin Cardiol, 2003. 26(1 Suppl 1): p. I11-4.
• Mitani, H., K. Egashira, and M. Kimura, HMG-CoA reductase inhibitor, fluvastatin, has cholesterol-lowering independent "direct" effects on atherosclerotic vessels in high cholesterol diet-fed rabbits. Pharmacol Res, 2003. 48(5): p. 417-27.
• Yamaguchi, Y., et al., Fluvastatin reduces modification of low-density lipoprotein in hyperlipidemic rabbit loaded with oxidative stress. Eur J Pharmacol, 2002. 436(1-2): p. 97-105.
• Sevin, G., et al., Different responses of fluvastatin to cholesterol-induced oxidative modifications in rabbits: evidence for preventive effect against DNA damage. Cell Biochem Funct, 2013. 31(4): p. 325-32.
• Yamanouchi, D., et al., Hydrophilic statin suppresses vein graft intimal hyperplasia via endothelial cell-tropic Rho-kinase inhibition. J Vasc Surg, 2005. 42(4): p. 757-64.
• Soma, M.R., et al., HMG CoA reductase inhibitors. In vivo effects on carotid intimal thickening in normocholesterolemic rabbits. Arterioscler Thromb, 1993. 13(4): p. 571-8.
• Janic, M., et al., Sub-therapeutic doses of fluvastatin and valsartan are more effective than therapeutic doses in providing beneficial cardiovascular pleiotropic effects in rats: A proof of concept study. Vascul Pharmacol, 2017. 99: p. 45-52.
• Lunder, M., et al., The effects of low-dose fluvastatin and valsartan combination on arterial function: a randomized clinical trial. Eur J Intern Med, 2012. 23(3): p. 261-6.
• Vanhoutte, P.M., et al., Endothelial dysfunction and vascular disease - a 30th anniversary update. Acta Physiol (Oxf), 2017. 219(1): p. 22-96.
• Kockx, M.M., et al., The endothelium during cuff-induced neointima formation in the rabbit carotid artery. Arterioscler Thromb, 1993. 13(12): p. 1874-84.
• Nicholls, S.J., et al., Reconstituted high-density lipoproteins inhibit the acute pro-oxidant and proinflammatory vascular changes induced by a periarterial collar in normocholesterolemic rabbits. Circulation, 2005. 111(12): p. 1543-50.
• Sugano, R., et al., Polymorphonuclear leukocytes may impair endothelial function: results of crossover randomized study of lipid-lowering therapies. Arterioscler Thromb Vasc Biol, 2005. 25(6): p. 1262-7.
• Sevin, G., et al., Low-dose fluvastatin prevents the functional alterations of endothelium induced by short-term cholesterol feeding in rabbit carotid artery. ScientificWorldJournal, 2012. 2012: p. 671728.
• Jin, Y., et al., Statins decrease lung inflammation in mice by upregulating tetraspanin CD9 in macrophages. PLoS One, 2013. 8(9): p. e73706.
• Kockx, M.M., et al., Triphasic sequence of neointimal formation in the cuffed carotid artery of the rabbit. Arterioscler Thromb, 1992. 12(12): p. 1447-57.
• Storino Farina, M., et al., Statins and atherosclerosis: the role of epigenetics. Medwave, 2015. 15(10): p. e6324.