title: Sarcoplasmic reticulum genes are selectively down-regulated in cardiomyopathy produced by doxorubicin in rabbits.
abstract: The clinical utility of doxorubicin, an antineoplastic agent, is limited by its cardiotoxicity. Our objective was to determine whether expression of genes encoding proteins that affect Ca2+ homeostasis were altered in the hearts of rabbits chronically treated with doxorubicin. Twelve male New Zealand white rabbits received an injection of doxorubicin (2.5 mg/kg i.v.) once a week for 8 weeks. Eight rabbits were similarly injected with saline as controls. The cardiac function of both groups was evaluated 8 weeks after the final injection, as were the levels of expression of mRNA for Ca2+ transport proteins in the sarcoplasmic reticulum and plasma membrane. The amount of the sarcoplasmic reticulum Ca2+-ATPase and the Ca2+ uptake capacity of the protein were also quantitated. Cardiac output was significantly decreased in the doxorubicin-treated group (71+/-21 ml/min, P<0.05) compared with the control group (118+/-15 ml/min). The mRNA levels for the sarcoplasmic reticulum proteins were significantly diminished in the doxorubicin-treated hearts: ryanodine receptor-2 (relative expression level compared with controls, 0.35+/-0.13, P<0.01), sarcoplasmic reticulum Ca2+-ATPase (0.56+/-0.13, P<0.01), phospholamban (0.62+/-0.20, P<0.01) and cardiac calsequestrin (0. 57+/-0.26, P<0.01). In addition, both relative amount of sarcoplasmic reticulum Ca2+-ATPase protein (doxorubicin-treated group, 69+/-17% of control, P<0.01) and the Ca2+ uptake capacity (46. 9+/-9.8 nmol Ca2+/mg protein-5 min in doxorubicin group v 63.2+/-10. 4 in the control group, P<0.01) were concomitantly decreased with its mRNA expression level. Conversely, the mRNA levels for the plasma membrane proteins did not differ from those of control rabbits: the dihydropyridine receptor (relative expression level, 1. 03+/-0.30, N.S.), plasma membrane Ca2+-ATPase (0.93+/-0.33, N.S.) and the Na+/Ca2+ exchanger (0.87+/-0.34, N.S.). These findings suggest that a selective decrease in mRNA expression for sarcoplasmic reticulum Ca2+ transport proteins is responsible for the impaired Ca2+ handling, and thus, for the reduced cardiac function seen in the cardiomyopathy induced in rabbits by the long-term treatment with doxorubicin.
authors.affiliation: Second Department of Internal Medicine, Gunma University School of Medicine, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Arai
authors.forename: K
authors.initials: K
authors.lastname: Tomaru
authors.forename: T
authors.initials: T
authors.lastname: Takizawa
authors.forename: K
authors.initials: K
authors.lastname: Sekiguchi
authors.forename: T
authors.initials: T
authors.lastname: Yokoyama
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
authors.forename: R
authors.initials: R
authors.lastname: Nagai
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D020746:Calcium Channels, L-Type; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000235:genetics* / Q000503:physiopathology; D002462:Cell Membrane / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000633:toxicity*; D006321:Heart / Q000187:drug effects; D017136:Ion Transport / Q000187:drug effects; D008297:Male; D009206:Myocardium / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D012333:RNA, Messenger; D019831:Sodium-Calcium Exchanger; D004317:Doxorubicin; D000252:Calcium-Transporting ATPases; D002118:Calcium