A novel transgenic mouse model reveals deregulation of the ubiquitin-proteasome system in the heart by doxorubicin.
Ubiquitin-proteasome system (UPS) mediated proteolysis is responsible for the degradation of majority of cellular proteins, thereby playing essential roles in maintaining cellular homeostasis and regulating a number of cellular functions. UPS dysfunction was implicated in the pathogenesis of numerous disorders, including neurodegenerative disease, muscular dystrophy, and a subset of cardiomyopathies. However, monitoring in vivo functional changes of the UPS remains a challenge, which hinders the elucidation of UPS pathophysiology. We have recently created a novel transgenic mouse model that ubiquitously expresses a surrogate protein substrate for the UPS. The present study validates its suitability to monitor in vivo changes of UPS proteolytic function in virtually all major organs. Primary culture of cells derived from the adult transgenic mice was also developed and tested for their applications in probing UPS involvement in pathogenesis. Applying these newly established in vivo and in vitro approaches, we have proven in the present study that doxorubicin enhances UPS function in the heart and in cultured cardiomyocytes, suggesting that UPS hyper-function may play an important role in the acute cardiotoxicity of doxorubicin therapy.
Kumarapeli
Asangi R K
AR
Cardiovascular Research Institute, South Dakota Health Research Foundation, Sioux Falls, South Dakota 57105, USA.
Horak
Kathleen M
KM
Glasford
Joseph W
JW
Li
Jie
J
Chen
Quanhai
Q
Liu
Jinbao
J
Zheng
Hanqiao
H
Wang
Xuejun
X
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002460:Cell Line; D004317:Doxorubicin / Q000494:pharmacology*; D004452:Echocardiography; D004591:Electrophoresis, Polyacrylamide Gel; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013050:Spectrometry, Fluorescence; D013997:Time Factors; D025801:Ubiquitin / Q000737:chemistry*
D000903:Antibiotics, Antineoplastic; D011480:Protease Inhibitors; D025801:Ubiquitin; D049452:Green Fluorescent Proteins; D004317:Doxorubicin; D046988:Proteasome Endopeptidase Complex