| Lovastatin-induced cardiac toxicity involves both oncotic and apoptotic cell death with the apoptotic component blunted by both caspase-2 and caspase-3 inhibitors. | |
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MedLine Citation:
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PMID: 14678744 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The objective of this study was to evaluate the cardiac toxicity of the HMG-CoA reductase inhibitors by testing the hypothesis that lovastatin induces apoptotic and/or oncotic cell death in the myocyte element of the heart and further that cell death is mediated through interruption of the mevalonate pathway and that apoptosis is induced through activation of caspase-2 and caspase-3. Cardiomyocytes were cultured from embryonic chick heart. Lovastatin-induced apoptosis in these cells was demonstrated by three independent techniques, namely (1) FACS analysis of low DNA content by propidium iodide (PI); (2) microscopic assessment for cellular changes of apoptosis; and (3) FACS analysis of cells stained with PI and fluorescein diacetate. Lovastatin produced a concentration-dependent increase in apoptotic cell death and 100 microM lovastatin showed over a 4-fold increase in apoptosis compared to control. Lovastatin also induced oncotic cell death, as there was a 2.5-fold increase in the amount of oncotic cell death compared to control. Lovastatin-induced apoptosis operated, in part, through the mevalonate pathway. The caspase-2 inhibitor z-VDVAD-fmk and the caspase-3 inhibitor Ac-DEVD-CHO reduced the extent of lovastatin-induced cardiac apoptosis. In contrast, lovastatin-induced oncosis was not only insensitive to these caspase-2 or -3 inhibitors but occurred through a mevalonate-independent mechanism of action. In summary, lovastatin-induced cardiotoxicity is complex and represents the sum of two distinct modes of cell death operating in part through the mevalonate pathway with the apoptotic component subject to modification by inhibitors of the initiator caspase, caspase-2, as well as the effector caspase, caspase-3. |
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Authors:
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Simon W Rabkin; Jennifer Y Kong |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Toxicology and applied pharmacology Volume: 193 ISSN: 0041-008X ISO Abbreviation: Toxicol. Appl. Pharmacol. Publication Date: 2003 Dec |
Date Detail:
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Created Date: 2003-12-17 Completed Date: 2004-01-12 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0416575 Medline TA: Toxicol Appl Pharmacol Country: United States |
Other Details:
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Languages: eng Pagination: 346-55 Citation Subset: IM |
Affiliation:
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University of British Columbia, Vancouver, British Columbia, V5Z 3J5 Canada. rabkin@interchange.ubc.ca |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / drug effects* Caspase 2 Caspase 3 Caspases / antagonists & inhibitors* Cells, Cultured Chick Embryo Cysteine Proteinase Inhibitors / pharmacology DNA / metabolism Flow Cytometry Hydroxymethylglutaryl-CoA Reductase Inhibitors / toxicity* Lovastatin / toxicity* Microscopy, Fluorescence Myocytes, Cardiac / drug effects*, enzymology, metabolism Propidium |
| Chemical | |
Reg. No./Substance:
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0/Cysteine Proteinase Inhibitors; 0/Hydroxymethylglutaryl-CoA Reductase Inhibitors; 36015-30-2/Propidium; 75330-75-5/Lovastatin; 9007-49-2/DNA; EC 3.4.22.-/Caspase 2; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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