Document Detail


Cisplatin compromises myocardial contractile function and mitochondrial ultrastructure: role of endoplasmic reticulum stress.
MedLine Citation:
PMID:  19878217     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Heng Ma; Kyla R Jones; Rui Guo; Peisheng Xu; Youqing Shen; Jun Ren
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-10-29
Journal Detail:
Title:  Clinical and experimental pharmacology & physiology     Volume:  37     ISSN:  1440-1681     ISO Abbreviation:  Clin. Exp. Pharmacol. Physiol.     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-04-22     Completed Date:  2010-08-06     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0425076     Medline TA:  Clin Exp Pharmacol Physiol     Country:  Australia    
Other Details:
Languages:  eng     Pagination:  460-5     Citation Subset:  IM    
Affiliation:
Division of Pharmaceutical Science, Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY 82071, USA. hma2@uwyo.edu
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MeSH Terms
Descriptor/Qualifier:
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:
5P20RR016474/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
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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