Doxorubicin and C-13 deoxydoxorubicin effects on ryanodine receptor gene expression.
Chronic anthracycline administration to rabbits causes impairment of cardiac contractility and decreased gene expression of the calcium-induced calcium release channel of sarcoplasmic reticulum (SR), the ryanodine receptor (RYR2). The C-13 hydroxy metabolite (doxorubicinol), formed in the heart, has been hypothesized to contribute to anthracycline cardiotoxicity. C-13 deoxydoxorubicin is an analog unable to form the C-13 hydroxy metabolite. Therefore, doxorubicin, C-13 deoxydoxorubicin, or saline was administered to rabbits (1 mg/kg iv twice weekly for 8 weeks). Left ventricular fractional shortening (LVFS) was decreased by chronic treatment with doxorubicin (28 +/- 2%; P < 0.05), but not C-13 deoxydoxorubicin (33 +/- 2%) compared to age-matched pair-fed controls. Doxorubicin, but not C-13 deoxydoxorubicin, caused a significant reduction (P < 0.02) in the ratio of RYR2/Ca-Mg ATPase (SERCA2) mRNA levels (0.57 +/- 0.1 vs 1.22 +/- 0.2, respectively) in the left ventricle. This suggests that doxorubicinol may contribute to the downregulation of cardiac RYR2 expression in chronic doxorubicin cardiotoxicity.
Gambliel
Herve A
HA
Department of Research and Development, Department of Veteran's Affairs Medical Center, Boise, Idaho 83702, USA.
Burke
Briant E
BE
Cusack
Barry J
BJ
Walsh
Gerald M
GM
Zhang
Yumei L
YL
Mushlin
Philip S
PS
Olson
Richard D
RD
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction; D012333:RNA, Messenger / Q000096:biosynthesis; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology
D000903:Antibiotics, Antineoplastic; C450719:C-13 deoxydoxorubicin; D012333:RNA, Messenger; D019837:Ryanodine Receptor Calcium Release Channel; D004317:Doxorubicin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases