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characteized by a significant decrease in the CRABP II expression which was prevented by probucol suggesting the restoration of retinoic acid metabolism as well as signaling. YII. Bax and Bcl-xl exPression Most important proteins, involved in the regulation of apoptosis, are Bax and Bclxl (Adams and Cory 1998; Huang et al. 1998). Increased expression of Bax protein leads to changes in the mitochondrial membrane transition potential, thereby resulting in the leakage of cytochrome C from mitochondria to cytosol, leading to the activation of downstream caspases and thus apoptosis (Desagher and Martinou 2000; Shimizu et al. 2000)' In contrast, an increased expression of anti-apoptotic protein Bcl-xl results in the stabilization of mitochondrial membrane potential thus preventing cytochrome C release and apoptosis (Hu et al. 1998; Huang and Chou 1998). ln this study the development of adriamycin-induced cardiomyopathy was accompanied by a significant increase in the expression of Bax and a significant decrease in Bcl-xl proteins resulting in a significant increase in the Bax/Bcl-xl ratio. These data are complemented by the in vitro studies as well, where adriamycin resulted in a significant increase in Bax and a decrease in the Bclxl levels. These changes also reflected as in increase in the BaxlBcl-xl ratio, which was associated with an increase apoptosis. The administration of probucol to the adriamycin gtoup animals resulted in a significant decrease in Bax, a significant increase in the Bcl-xl levels and a significant decrease in the BaxlBcl-xl ratio. Since probucol is shown to protect against adriamycininduced heart failure, this protection, at least in part, may be due to the prevention of adriamycin-induced apoptosis in cardiac myocytes. Antioxidant trolox in isolated cardiac myocytes also modulated adriamycin-induced increase in Bax and decrease in Bcl-xl t28
expression. These effects of trolox caused a significant decrease in the Bax/Bcl-xl ratio when compared to the ADR group. Thus, both in vivo and in vitro studies support the hypothesis that the administration of antioxidants, probucol and trolox, resulted in a protection against adriamycin-induced apoptosis. The effect is likely due to a decrease in oxidative stress, decrease in RAR/RXR receptor ratio, reduced expression of apoptotic factors, thus preventing adriamycin-induced ap opto si s. Retinoic acid (0.1pM) addition to the adriamycin caused a decrease in Bax, a signif,rcant increase in the Bcl-xl expression and a decrease in BaxlBcl-xl ratio thus exerting an anti-apoptotic effects. The administration of 1 pM retinoic acid, however, despite causing a decrease in oxidative stress, caused a significant increase in the Bax and Bcl-xl protein levels with a net increase in the increase in Bax/Bcl-xl ratio. As stated earlier this effect of high concentrations of retinoic acid may be due to some direct activation of its receptors. Taken together, these findings lend support to the hypothesis put forward in this study. t29
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il\VOLVEMENT OF RETII\OIC ACID II{
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Title: AKNOWLEDGMENTS DEDICATION LI
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IV.b.3. The uptake to peripheral ti
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II.a. Total RAR and total RXR recep
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ACKNO\ryLEDGMENTS I must say that m
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DEDICATION To my toughest critic, m
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Figure: LIST OF FIGURES Page: 1. Ch
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30. A and B The expression of anti-
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treated (ADR), trolox treated (TROL
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INTRODUCTION Adriamycin, an anthrac
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apoptosis, which will ultimately pr
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LITERATURE REVIE\il I. Adriamycin i
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Binding and alkylation of DNA Inter
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myocardial inflammation which was s
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1990; Kusuoka et al. l99l; Olson et
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levels of antioxidant enzymes (Odom
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causing the increased leakage of el
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mechanisms which are involved in th
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to protect against adriamycin-induc
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The usage of Probucol.' Most promis
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II. Oxidative stress II.a. Introduc
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of a large array of cellular abnorm
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menstruation (Kokawa et al. 1996),
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DNA(Cohen 1997; Saikumar et al. 199
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pathogenesis of heart failure. A nu
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elonging to spontaneous hlpertensiv
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AlþTrsns Retlnolc Acld fAfRAl g€
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dehydrogenase (SDR), alcohol dehydr
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(Bavik et a|. 1991). Soon after its
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et al. 1994; Napoli 1996). The func
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is achieved through its binding to
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Retinoic acid signaling pathwaybegi
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(Bavik et al. 1997). One of the mos
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cells (Gaetano et ai. ZOot¡. The s
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neuroblastoma, genn cell tumors and
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presence of two distinctive pathway
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cytochrome C release from mitochond
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peroxidation (Sultana et a|.2004).
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adipose tissue and to a lesser exte
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such as; increased generation of re
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physiological and pathological proc
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Protective effects of PPAR y agonis
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IIYPOTHESIS This study tests the hy
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I.c.Collection of Tissues Hearts we
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thoracotomy was performed and heart
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Il.c.Western Blot Analvsis Western
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green were counted as dead cells. T
Page 96 and 97: RESULTS I.In Vivo Studies I.a.Gener
Page 101: Lc. Retinoic acid receptors Three w
Page 108: The RAR o and PPAR-õ receptors RNA
Page 113 and 114: significantly decreased when compar
Page 116: IL b.7. RAR alPha recePtor levels T
Page 120: ILb. 3. RAR sammø recEtor levels F
Page 124: ILb. 5. RXR baa recEúor levels The
Page 129: visible staining were accounted as
Page 137 and 138: DISSCUSION I. Adriamvcin CardiomvoP
Page 139 and 140: Treatment with adriamycin has been
Page 141 and 142: High RA 1 Adriamycin I oxidative st
Page 143 and 144: study as well as in others (Kumar e
Page 145: It is reported that PPAR y receptor
Page 149 and 150: REFERENCES Abdul Hamied,T.A., D.Par
Page 151 and 152: Bashor,M.M., D.O.Toft, and F.Chytll
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