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examined all these individual receptors with multitude of interventions including different concentrations of adriamycin (4,8 and 10 pM), different concentrations of retinoic acid (0.1 and lpM), lipid soluble antioxidant (probucol) and water soluble antioxidant (trolox). These data revealed multiple of specific changes in the listed isoforms of retinoic acid receptors. Because of different directionalities of there changes, it is difficult to make a simple conclusion. However, PROB group data provide an indication that changes in the RA receptors can be brought about not only through the modification of gene expression but also through direct membrane as well as lipid changes due to these interventions. Thus further detailed studies are required for each of the isoforms to fully understand the significance of different isoforms. It is important to state that a study of the ratio of total RAR and total RXR, as is done here, provides avery clear cut message that an increase in this ratio correlates with an increase in Bax/Bcl-xl ratio and such an increase is promoted by an increase in oxidative stress. Based on the data obtained in my study as well as on the information available in literature, it is established that adriamycin induces oxidative stress. The latter influences the expression of RAR and RXR receptors such that the ratio of RAR/RXR is increased. This increase in receptor ratio modifies both proapoptotic and antiapoptotic proteins, Bax and Bcl-xl respectively to cause an increase in apoptosis. Interference in this proposed chain of events (Fig. 33) with appropriate antioxidant therapy in this study is shown to reduce apoptosis. 122
High RA 1 Adriamycin I oxidative stress ¡ Probucol . Trolox ¡ LowRA I RARYRXR Receptor Ratio PPARr and PPAR õ I 1 Bax/Bcl-xl I 1 Apoptosis I Adriamycin-lnduced Heart Failure and Congestive Heart Failure Fig.33: Proposed pathway of the role of retinoic acid in the pathogenesis of adriamycin induced apoptosis and congestive heart failure. RA-retinoic acid; RAR-retinoic acid receptors; RXR-retinoic acid X receptors; PPAR-peroxisome proliferation activator receptor. t23
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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
Page 90 and 91: thoracotomy was performed and heart
Page 92 and 93: Il.c.Western Blot Analvsis Western
Page 94 and 95: 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: Treatment with adriamycin has been
Page 143 and 144: study as well as in others (Kumar e
Page 145 and 146: It is reported that PPAR y receptor
Page 147 and 148: expression. These effects of trolox
Page 149 and 150: REFERENCES Abdul Hamied,T.A., D.Par
Page 151 and 152: Bashor,M.M., D.O.Toft, and F.Chytll
Page 153 and 154: distribution of PPAR-alpha, -beta,
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Page 157 and 158: Diep,Q.N., M'El Mabrouk, J.S.Cohn,
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wi1liams,J.B. and J.L.Napoli. 1985.
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peroxisome proliferator-activated r
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