title: Doxorubicin induces sarcoplasmic reticulum calcium regulation dysfunction via the decrease of SERCA2 and phospholamban expressions in rats.
abstract: This study aims to explore the changes in calcium regulation in the sarcoplasmic reticulum (SR) during doxorubicin (DOX) treatment. Sprague-Dawley rats were treated with intravenous DOX (1.5 mg/kg) twice weekly for 12 treatments. The hemodynamic changes, myocardial oxidative stress, levels of cardiac toxicity markers, and calcium handling of the myocardial SR were observed. When the accumulation of DOX reached 12 mg/kg, (1) heart weight, left ventricular mass, and lung congestion increased significantly, and ascites appeared; (2) SBP, DBP, MAP, +dP/dt, -dP/dt, and LVSP decreased significantly, and LVEDP increased (p < 0.01); (3) the iNOS activity and MDA and NO concentrations significantly increased, while the SOD decreased (p < 0.05 or 0.01); (4) the serum level of the AST, LDH CPK, cTnI, and BNP increased significantly (p < 0.01); (5) during DOX treatment, the rat SR Ca(2+) absorption function and Ca(2+)-stimulated ATPase activity declined dramatically, as did the SERCA2 and phospholamban levels (p < 0.01). As expected, all these changes became evident with DOX accumulation in vivo (p < 0.05 or 0.01). In conclusion, DOX induces SR calcium regulation dysfunction via the decrease of SERCA2 and phospholamban expressions in rats.
authors.affiliation: Division of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kong Jiang Road, Shanghai, 200092, China, zhangyachen1965@126.com.
authors.forename: Yachen
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Yong
authors.initials: Y
authors.lastname: Tang
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Xie
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Huang
authors.forename: Yigang
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D009202:Cardiomyopathies / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D004317:Doxorubicin / Q000633:toxicity*; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D009569:Nitric Oxide / Q000097:blood; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010088:Oxidoreductases / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D012519:Sarcoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*; D000099211:Phospholamban
chemical_list: D000903:Antibiotics, Antineoplastic; D002118:Calcium; D002135:Calcium-Binding Proteins; D004317:Doxorubicin; D008315:Malondialdehyde; D009569:Nitric Oxide; D010088:Oxidoreductases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban; C506948:Atp2a2 protein, rat