| Cisplatin compromises myocardial contractile function and mitochondrial ultrastructure: role of endoplasmic reticulum stress. | |
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MedLine Citation:
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PMID: 19878217 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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1. Cisplatin is a potent chemotherapeutic agent with broad-spectrum antineoplastic activity against various types of tumours. However, a major factor limiting treatment with cisplatin is its acute and cumulative cardiotoxicity. The aim of the present study was to explore the effect of cisplatin on myocardial contractile function and the possible underlying cellular mechanisms. 2. C57 mice were treated with cisplatin (10 mg/kg per day, i.v.) or vehicle (0.9% NaCl) for 1 week and myocardial function was assessed using the Langendorff and cardiomyocyte edge-detection systems. Transmission electron microscopy, mitochondrial membrane potential, indices of endoplasmic reticulum (ER) stress and caspase 3 activity were evaluated. 3. Cisplatin-treated mice developed myocardial contractile dysfunction, as evidenced by a reduction in left ventricular developed pressure (LVDP) and the first derivative of LVDP (+/-dP/dt). Cisplatin treatment significantly prolonged time to 90% relengthening, depressed peak shortening, maximal velocity of shortening/relengthening (+/-dL/dt) and augmented the frequency-elicited depression in peak shortening. The JC-1 fluorescent assay demonstrated that cispatin-induced cardiac dysfunction was associated with mitochondrial membrane depolarization. Transmission electron microscopy revealed that cisplatin induces ultrastructural abnormalities of the mitochondria. Following cisplatin treatment, cardiomyocytes show activation of the ER stress response, increased caspase 3 activity and increased terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL) staining. 4. The data indicate that cisplatin is cardiotoxic and may lead to left ventricular dysfunction and depressed cardiomyocyte contraction associated with mitochondrial abnormalities, enhanced ER stress and apoptosis. This work should shed some light on the management of cisplatin-induced cardiac injury. |
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Authors:
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Heng Ma; Kyla R Jones; Rui Guo; Peisheng Xu; Youqing Shen; Jun Ren |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2009-10-29 |
Journal Detail:
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Title: Clinical and experimental pharmacology & physiology Volume: 37 ISSN: 1440-1681 ISO Abbreviation: Clin. Exp. Pharmacol. Physiol. Publication Date: 2010 Apr |
Date Detail:
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Created Date: 2010-04-22 Completed Date: 2010-08-06 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0425076 Medline TA: Clin Exp Pharmacol Physiol Country: Australia |
Other Details:
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Languages: eng Pagination: 460-5 Citation Subset: IM |
Affiliation:
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Division of Pharmaceutical Science, Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY 82071, USA. hma2@uwyo.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antineoplastic Agents / toxicity* Apoptosis / drug effects Cardiotoxins / toxicity* Caspase 3 / metabolism Cell Shape / drug effects Cells, Cultured Cisplatin / toxicity* Depression, Chemical Endoplasmic Reticulum / drug effects*, ultrastructure Heart / drug effects Hemodynamics / drug effects Male Membrane Potential, Mitochondrial / drug effects Mice Mice, Inbred C57BL Mitochondria, Heart / drug effects*, ultrastructure Myocardial Contraction / drug effects* Myocardium / cytology, pathology Myocytes, Cardiac / drug effects, enzymology, physiology, ultrastructure Organ Size / drug effects Stress, Physiological / drug effects* |
| Grant Support | |
ID/Acronym/Agency:
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5P20RR016474/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Cardiotoxins; 15663-27-1/Cisplatin; EC 3.4.22.-/Caspase 3 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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