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APPROACH MATERIALS AND METHODS l. In Vivo studies I.a. Animal treatment I.b. Hemodynamic assessment I.c. Collection of tissues I.d.'Western Blot analysis on whole heart samples I.e. Affymetrix gene-chip probe array analyses 68 69 69 69 69 70 70 7T IL In Vitro Studies II.a. Adult cardiac myocytes isolation II.b. Cell treatment II.c. Western blot analysis II.d. Arurexin-propidium iodide assay ILe. Oxidative stress studies 7l 7I t) 74 75 76 III. Protein Assessment and Statistical Analysis RESULTS I. In Vivo Studies La. General observations Lb. Hemodynamic studies Lc. Retinoic acid receptors I.d. Bax and Bcl-xl expression in the hearts of treated animals I.e. PPAR-ô receptor expression in hearts of treated animals I.f. Afffrnetrix gene-chip probe anay analyses of the hearts 77 78 78 78 80 83 86 89 90 IL In Vítro Studies 92 1V
II.a. Total RAR and total RXR receptor levels II.a.1. 4 pM Adriamycin Treatment II.a.2. 8¡rM Adriamycin Treatment ll.a.3. 10 ¡rM Adriamycin Treatment II.b. Retinoic acid receptor dynamics in isolated cardiac myocytes II. b.1. RAR alpha receptor levels ILb.z. RAR beta receptor levels II.b.3. RAR gamma receptor levels ILb.4. RXR alpha receptor levels II.b.5.RXR beta receptor levels II.b.6.RXR gamma receptor levels 92 94 95 95 97 98 i00 r02 104 106 108 II.c. Effects of interventions on apoptosis in isorated cardiac myocytes II.d. oxidative stress measurements in treated isolated cardiac myocytes II.e. Pro and anti-apoptotic protein expression IL e.1 Bax levels IL e.2. Bcl-xl expression IL e.3. Bax/Bcl ratio ILf, PPAR-delta levels 1i0 1.1 3 rt4 i 15 TL6 117 118 DISCUSION L Adriamycin Cardiomyopathy II. Animal model III. The occurrence of oxidative stress and apoptosis IV. RAR/RXR receptor ratio and its significance 119 t19 119 t20 121
Page 1 and 2: il\VOLVEMENT OF RETII\OIC ACID II{
Page 3 and 4: Title: AKNOWLEDGMENTS DEDICATION LI
Page 5: IV.b.3. The uptake to peripheral ti
Page 9 and 10: ACKNO\ryLEDGMENTS I must say that m
Page 11 and 12: DEDICATION To my toughest critic, m
Page 13 and 14: Figure: LIST OF FIGURES Page: 1. Ch
Page 15 and 16: 30. A and B The expression of anti-
Page 17 and 18: treated (ADR), trolox treated (TROL
Page 19 and 20: INTRODUCTION Adriamycin, an anthrac
Page 21 and 22: apoptosis, which will ultimately pr
Page 23 and 24: LITERATURE REVIE\il I. Adriamycin i
Page 25 and 26: Binding and alkylation of DNA Inter
Page 27 and 28: myocardial inflammation which was s
Page 29 and 30: 1990; Kusuoka et al. l99l; Olson et
Page 31 and 32: levels of antioxidant enzymes (Odom
Page 33 and 34: causing the increased leakage of el
Page 35 and 36: mechanisms which are involved in th
Page 37 and 38: to protect against adriamycin-induc
Page 39 and 40: The usage of Probucol.' Most promis
Page 41 and 42: II. Oxidative stress II.a. Introduc
Page 43 and 44: of a large array of cellular abnorm
Page 45 and 46: menstruation (Kokawa et al. 1996),
Page 47 and 48: DNA(Cohen 1997; Saikumar et al. 199
Page 49 and 50: pathogenesis of heart failure. A nu
Page 51 and 52: elonging to spontaneous hlpertensiv
Page 53 and 54: AlþTrsns Retlnolc Acld fAfRAl g€
Page 55 and 56: dehydrogenase (SDR), alcohol dehydr
Page 57 and 58:
(Bavik et a|. 1991). Soon after its
Page 59 and 60:
et al. 1994; Napoli 1996). The func
Page 61:
is achieved through its binding to
Page 64 and 65:
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
Page 72 and 73:
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
Page 88 and 89:
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
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RESULTS I.In Vivo Studies I.a.Gener
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Lc. Retinoic acid receptors Three w
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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
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DISSCUSION I. Adriamvcin CardiomvoP
Page 139 and 140:
Treatment with adriamycin has been
Page 141 and 142:
High RA 1 Adriamycin I oxidative st
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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
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distribution of PPAR-alpha, -beta,
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colbert,M.C., D.G.Hall, T.R.Kimball
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Diep,Q.N., M'El Mabrouk, J.S.Cohn,
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Evans,R.M. 1988. "The steroid and t
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Ghione M. Development of Adriamycin
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Herman,E., R.Young, and S.Krop . Ig
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morphogenetic protein-2 inhibits se
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Khandoudi,N., P.Delerive, I.Berrebi
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Kusuoka,H., S.Futaki, Y.Koretsune,
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and myosin heavy chain gene express
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Mehta,J.L., B.Hu, J.Chen, and D.Li.
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Morriss-Kay,G.M. and s.J.ward. 1999
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Notario,B., M.Zamora, O.Vinas, and
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petkovich,M., N.J.Brand, A.Krust, a
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Ruberte,E., P.Dolle, P.Chambon, and
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Sharov,V.G., H.N.Sabbah, H.Shimoyam
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spiegelman,B.M. and J.s.Flier .1996
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Teebor,G.w., R.J.Boorstein, and J.c
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vanVeen,T.A.,H.V.vanRijen,R.F.V/ieg
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wi1liams,J.B. and J.L.Napoli. 1985.
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peroxisome proliferator-activated r
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