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16. Changes in the total RAR receptor levels in ADR, ADR+TROL, ADR+0.1R4 and ADR+IRA group myocytes 93 17. Changes in the total RXR receptor levels in ADR, ADR+TROL, ADR+0.1R4 and ADR+IRA group myocytes 93 18. Changes in the RAR/RXR ratio in ADR, ADR+TROL, ADR+0.1R4 and ADR+IRA group myocytes 94 19. A and B Changes in the RAR alpha receptors in ADR, ADR+TROL, ADR+0.1R4 and ADR+IRA group myocytes 97 20. A and B Changes in the RAR beta receptors in ADR, ADR+TROL, ADR+0.1R4 and ADR+IRA group myocytes gg 2I. A and B Changes in the RAR gamma receptors in ADR, ADR+TROL, ADR+0.1R4 and ADR+IRA group myocytes 101 22. ^ and B Changes in the RXR alpha receptors in ADR, ADR+TROL, ADR+0.1R4 and ADR+IRA group myocytes 103 23. A and B Changes in the RXR beta receptor levels in ADR, ADR+TROL, ADR+0.1R4 and ADR+iRA group myocyres 105 24. A and B Changes in the RXR gamma receptor levels in ADR, ADR+TROL, ADR+0.1R4 and ADR+IRA group myocyres lO7 25. Annexin and PI assay identification of apoptotic cells in coNT, ADR, 0.1R4, ADR+0.1R4, lRA, ADR+IRA, and ADR+TROL group isolated cardiac myocytes 109 26. Occurrence of apoptosis in CONT, ADR, 0.1 RA, ADR+O.1 RA, 1 RA, ADR+IRA and ADR and TROL group isolated myocytes 110 2T.Detectton of Oxidative stress by CM-H2 DCFDA assay in CONT, ADR, TROL, ADR+TROL, ADR+O,iRA and ADR+I RA group cardiac myocytes IT2 28. Occurrence of oxidative stress in CONT, ADR, 0.1 RA, ADR+0.1prq, 1 RA, ADR+IRA, TROL and ADR+TROL group isolated myocytes 113 29. A and B The expression of pro-apoptotic protein Bax in ADR, ADR+TROL, ADR+O.1R4 and ADR+iRA group myocytes 115 xll
30. A and B The expression of anti-apoptotic protein Bcl-xl in ADR, ADR+TROL, ADR+0.1R4 and ADR+IRA group myocytes 31. Changes in the BaxlBcl-xl ratio in ADR, ADR+TROL, ADR+O.1R4 and ADR+IRA group myocytes 32. A and B PPAR delta receptor levels in ADR, ADR+TROL, ADR+O.1R,{ and ADR+IRA group myocytes 33. Proposed pathway of the role of retinoic acid in the pathogenesis of adriamycin induced apoptosis and congestive heart failure i16 t17 118 123 xll1
Page 1 and 2: il\VOLVEMENT OF RETII\OIC ACID II{
Page 3 and 4: Title: AKNOWLEDGMENTS DEDICATION LI
Page 5 and 6: IV.b.3. The uptake to peripheral ti
Page 7 and 8: II.a. Total RAR and total RXR recep
Page 9 and 10: ACKNO\ryLEDGMENTS I must say that m
Page 11 and 12: DEDICATION To my toughest critic, m
Page 13: Figure: LIST OF FIGURES Page: 1. Ch
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
Page 66 and 67:
(Bavik et al. 1997). One of the mos
Page 68 and 69:
cells (Gaetano et ai. ZOot¡. The s
Page 70 and 71:
neuroblastoma, genn cell tumors and
Page 72 and 73:
presence of two distinctive pathway
Page 74 and 75:
cytochrome C release from mitochond
Page 76 and 77:
peroxidation (Sultana et a|.2004).
Page 78 and 79:
adipose tissue and to a lesser exte
Page 80 and 81:
such as; increased generation of re
Page 82 and 83:
physiological and pathological proc
Page 84 and 85:
Protective effects of PPAR y agonis
Page 86 and 87:
IIYPOTHESIS This study tests the hy
Page 88 and 89:
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 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 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,
Page 155 and 156:
colbert,M.C., D.G.Hall, T.R.Kimball
Page 157 and 158:
Diep,Q.N., M'El Mabrouk, J.S.Cohn,
Page 159 and 160:
Evans,R.M. 1988. "The steroid and t
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Ghione M. Development of Adriamycin
Page 163 and 164:
Herman,E., R.Young, and S.Krop . Ig
Page 165 and 166:
morphogenetic protein-2 inhibits se
Page 167 and 168:
Khandoudi,N., P.Delerive, I.Berrebi
Page 169 and 170:
Kusuoka,H., S.Futaki, Y.Koretsune,
Page 171 and 172:
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
Page 179 and 180:
petkovich,M., N.J.Brand, A.Krust, a
Page 181 and 182:
Ruberte,E., P.Dolle, P.Chambon, and
Page 183 and 184:
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.
Page 193 and 194:
peroxisome proliferator-activated r
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