3A and 3B)

3A and 3B). thickening and accompanying vascular dysfunction in early atherosclerosis without cholesterol loading. These beneficial effects of lacidipine Rabbit polyclonal to ERCC5.Seven complementation groups (A-G) of xeroderma pigmentosum have been described. Thexeroderma pigmentosum group A protein, XPA, is a zinc metalloprotein which preferentially bindsto DNA damaged by ultraviolet (UV) radiation and chemical carcinogens. XPA is a DNA repairenzyme that has been shown to be required for the incision step of nucleotide excision repair. XPG(also designated ERCC5) is an endonuclease that makes the 3 incision in DNA nucleotide excisionrepair. Mammalian XPG is similar in sequence to yeast RAD2. Conserved residues in the catalyticcenter of XPG are important for nuclease activity and function in nucleotide excision repair were not associated with changes in either MMP-9 expression or oxidant stress. However, enhanced endothelium dependent relaxations by lacidipine, suggest that vascular protective effects of nitric oxide may be at least partly, responsible from antiatherosclerotic effects of LLY-507 lacidipine Keywords:Lacidipine, MMP-9, Collar-induced atherosclerosis, Nitric oxide, Vascular reactivity, 5-HT sensitivity, Intimal thickening, Rabbit carotid artery == INTRODUCTION == Atherosclerosis is usually a cardiovascular disease characterized by an inflammatory process (Ross, 1999) that may result from endothelial damage, leading to intimal thickening, altered production of extracellular matrix protein and lipid deposition. Lacidipine, a potent antihypertensive Ca++channel blocker, has been shown to inhibit the development of atherosclerosis in hypercholesterolemic conditions (Berniniet al., 1993,P. Cristoforiet al., 2004a,P. Cristoforiet al., 2000,Somaet al., 1994,Somaet al., 1996,Zanchettiet al., 2002). Whether lacidipine prevents intimal thickening in the absence of cholesterol loading or altered lipid metabolism has not been reported yet. In this study we induced early atherosclerosis in rabbit carotid arteries using a silicon collar – a widely accepted model which does not induce hypercholesterolemia and hypertension but causes biochemical, morphological and functional changes much like those observed in the early stage of atherosclerosis in humans (Beesley J, 1992, Boothet al., 1989, Kerryet al., 2005, Yasaet al., 2007). The intimal thickening is generally accompanied by alterations in vascular reactivity, such as increased sensitivity to 5-hydroxytryptamine (5-HT) and decreased vasodilator responses to agonists (De Meyeret al., 1994, Kerryet al., 2005,Sobeyet al., 1991,Ustuneset al., 1996, Yasaet al., 2007). The effect of lacidipine on vascular dysfunction in early atherosclerosis was unclear. In previous studies the antiatherosclerotic effects of lacidipine has been attributed to its actions on modification of cholesterol metabolism (Bernini et al., 1991,Bernini et al., 1997,Bernini et al., 1993,Spieker & Zidek, 1995), amelioration of endothelial cell dysfunction (Zanchetti et al., 2004), enhanced activity of the NO system (P. G. Cristoforiet al., 2004b), antioxidant properties (P. Cristoforiet al., 2004a) or reduced expression of adhesion molecules (Zanchettiet al., 2004) or endothelin (P. Cristoforiet al., 2000) in hypercholesterolemic conditions. Later it has been shown that lacidipine also decreases the MMP (matrix metalloproteinase)-9 expression in macrophages (Bellostaet al., 2001). Several studies demonstrated a role of MMPs in atherogenesis and plaque stability (Brownet al., 1995,Galiset al., 1994). However, whether oxidant stress and MMP-9 is usually involved in possible antiatherosclerotic effects of lacidipine, in the absence of hypercholesterolemia in an early atherosclerosis model is not known. Accordingly, the primary goal of the present study was to determine whether lacidipine prevents the intimal thickening and vascular dysfunction induced by collaring in the absence of hypertension and hypercholesterolemia. A second goal was to determine whether and to what extent MMP-9 and oxidant stress are involved in the possible beneficial effects of lacidipine. == MATERIALS AND METHODS == == Treatment of animals == The animal experiments were carried out in accordance with guidelines described by the Ethics Committee of the Faculty of Pharmacy, Ege University or college. A total of 16 rabbits were used in this study. White rabbits (1.52 kg) of either sex were divided into 2 groups. The treatment protocol was as explained previously (Ustuneset al., 1996). Briefly, the first group received a single administration of lacidipine (5 mg/kg/day, dissolved in 2.5 ml 0.5% aqueous solution of methylcellulose) via a gastric feeding tube. The second group (placebo) received only the vehicle (0.5% methylcellulose, 2.5 ml/kg/day) by the same administration route. Throughout the 3 week-treatment period, each rabbit was kept in a separate cage and allowed to access regular diet (standard rabbit chow and tap water ad libitum). == Surgical procedure for induction of intimal LLY-507 thickening == After the 7th day of lacidipine or placebo treatment, the rabbits were anesthetized with sodium pentobarbital (30 mg/kg, i.v.). Subsequently, the left carotid artery was surgically utilized and surrounded by a LLY-507 non-occlusive, flexible silicone collar (Ustuneset al., 1996,Yasaet al., 1999). The collar was 2 cm in length slightly touching the outer surface of the artery on.