title: Cardiomyocyte specific ablation of p53 is not sufficient to block doxorubicin induced cardiac fibrosis and associated cytoskeletal changes.
abstract: Doxorubicin (Dox) is an anthracycline used to effectively treat several forms of cancer. Unfortunately, the use of Dox is limited due to its association with cardiovascular complications which are manifested as acute and chronic cardiotoxicity. The pathophysiological mechanism of Dox induced cardiotoxicity appears to involve increased expression of the tumor suppressor protein p53 in cardiomyocytes, followed by cellular apoptosis. It is not known whether downregulation of p53 expression in cardiomyocytes would result in decreased rates of myocardial fibrosis which occurs in response to cardiomyocyte loss. Further, it is not known whether Dox can induce perivascular necrosis and associated fibrosis in the heart. In this study we measured the effects of acute Dox treatment on myocardial and perivascular apoptosis and fibrosis in a conditional knockout (CKO) mouse model system which harbours inactive p53 alleles specifically in cardiomyocytes. CKO mice treated with a single dose of Dox (20 mg/kg), did not display lower levels of myocardial apoptosis or reactive oxygen and nitrogen species (ROS/RNS) compared to control mice with intact p53 alleles. Interestingly, CKO mice also displayed higher levels of interstitial and perivascular fibrosis compared to controls 3 or 7 days after Dox treatment. Additionally, the decrease in levels of the microtubule protein α-tubulin, which occurs in response to Dox treatment, was not prevented in CKO mice. Overall, these results indicate that selective loss of p53 in cardiomyocytes is not sufficient to prevent Dox induced myocardial ROS/RNS generation, apoptosis, interstitial fibrosis and perivascular fibrosis. Further, these results support a role for p53 independent apoptotic pathways leading to Dox induced myocardial damage and highlight the importance of vascular lesions in Dox induced cardiotoxicity.
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Tiam
authors.initials: T
authors.lastname: Feridooni
authors.forename: Adam
authors.initials: A
authors.lastname: Hotchkiss
authors.forename: Sarah
authors.initials: S
authors.lastname: Remley-Carr
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Saga
authors.forename: Kishore B S
authors.initials: KB
authors.lastname: Pasumarthi
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation; D003599:Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D005355:Fibrosis / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D005455:Fluorescent Antibody Technique; D006331:Heart Diseases / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D019426:Integrases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D000903:Antibiotics, Antineoplastic; D015415:Biomarkers; D017382:Reactive Oxygen Species; D014404:Tubulin; D016159:Tumor Suppressor Protein p53; D013481:Superoxides; D004317:Doxorubicin; C045073:Cre recombinase; D019426:Integrases