title: Hsp10 and Hsp60 modulate Bcl-2 family and mitochondria apoptosis signaling induced by doxorubicin in cardiac muscle cells.
abstract: The development of doxorubicin cardiomyopathy involves apoptosis of cardiac muscle cells. This study was carried out to define the roles of two heat-shock proteins, Hsp10 and Hsp60, on doxorubicin-induced apoptosis in primary cardiomyocytes. Doxorubicin induces apoptosis of cardiomyocytes by activating mitochondria apoptosis signaling. Transducing cardiomyocytes with Hsp10 or Hsp60 with adenoviral vector suppressed the occurrence of apoptosis in the doxorubicin-treated cardiomyocytes. Overexpression of Hsp10 and Hsp60 increased the abundance of the anti-apoptotic Bcl-xl and Bcl-2, and reduced the protein content of the pro-apoptotic Bax. Hsp60 overexpression also significantly reduced doxorubicin induction of Bad, whereas overexpression of Hsp10 did not alter the expression of Bad in the doxorubicin-treated cells. Overexpression of Hsp10 and Hsp60, respectively, stabilized mitochondrial cross-membrane potential, inhibited Caspase 3, and suppressed PARP. These findings indicate that overexpression of Hsp10 and Hsp60 differentially modulated Bcl-2 family and in turn attenuate doxorubicin-induced cardiac muscle death. The effects of Hsp10 and Hsp60 on Bcl-2 family could not be explained by the abundance of Bcl-2 family mRNA levels. Hsp60 interacted with Bcl-xl and Bax in the cardiomyocytes in vivo. The effect of Hsp10 and Hsp60 on the abundance of Bcl-xl could not be blocked by cycloheximide. Moreover, Hsp10 and Hsp60 inhibited ubiquitination of Bcl-xl. These findings suggest that Hsp10 and Hsp60 modulated post-translational modification of Bcl-xl. Antisense Hsp60 reduced the abundance of endogenous Hsp60 in cardiomyocytes and amplified the cytotoxicity of doxorubicin. These data provide a novel link between Hsp10/Hsp60 and cardiac protection in doxorubicin cardiomyopathy.
authors.affiliation: Department of Medicine, Biological Chemistry, Physiology and Biophysics, Center for Cardiovascular Hormone Research, University of California, Medical Science 1, Room C240, Irvine, CA 92697, USA.
authors.forename: Yue-Xin
authors.initials: YX
authors.lastname: Shan
authors.forename: Tsun-Jui
authors.initials: TJ
authors.lastname: Liu
authors.forename: Hou-Fen
authors.initials: HF
authors.lastname: Su
authors.forename: Ahmad
authors.initials: A
authors.lastname: Samsamshariat
authors.forename: Ruben
authors.initials: R
authors.lastname: Mestril
authors.forename: Ping H
authors.initials: PH
authors.lastname: Wang
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D009202:Cardiomyopathies / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism; D002478:Cells, Cultured; D018835:Chaperonin 10 / Q000378:metabolism*; D018834:Chaperonin 60 / Q000187:drug effects / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology / Q000633:toxicity; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein
chemical_list: C494821:Bad protein, rat; C494828:Bax protein, rat; C494813:Bcl2l1 protein, rat; D002352:Carrier Proteins; D018835:Chaperonin 10; D018834:Chaperonin 60; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D004317:Doxorubicin