Lovastatin-induced cardiac toxicity involves both oncotic and apoptotic cell death with the apoptotic component
Simon W Rabkin1, Jennifer Y Kong
1University of British Columbia, Vancouver, British Columbia, V5Z 3J5 Canada. rabkin@interchange.ubc.ca
Abstract:
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.
Insights
Lovastatin causes heart cell death through apoptosis and oncosis, partly via the mevalonate pathway. Apoptosis involves caspases-2 and -3, while oncosis is independent of these.
Area of Science:
- Cardiovascular Pharmacology
- Cellular Toxicology
- Molecular Cardiology
Background:
- HMG-CoA reductase inhibitors, like lovastatin, are widely used statins.
- Potential cardiac side effects of statins warrant thorough investigation.
- Understanding mechanisms of statin-induced cardiotoxicity is crucial for patient safety.
Purpose of the Study:
- To investigate lovastatin's cardiac toxicity.
- To determine if lovastatin induces apoptotic and/or oncotic cell death in cardiomyocytes.
- To elucidate the role of the mevalonate pathway and specific caspases in lovastatin-induced cell death.
Main Methods:
- Primary cardiomyocyte cultures from embryonic chick hearts.
- Flow cytometry (FACS) for DNA content analysis (propidium iodide staining).
- Microscopic evaluation of cellular morphology for apoptosis.
- Assessment of cell death with PI and fluorescein diacetate staining.
- Use of caspase-2 and caspase-3 inhibitors (z-VDVAD-fmk and Ac-DEVD-CHO).
Main Results:
- Lovastatin induced a concentration-dependent increase in both apoptotic and oncotic cell death in cardiomyocytes.
- Apoptotic cell death showed a >4-fold increase at 100 μM lovastatin.
- Oncotic cell death increased 2.5-fold compared to controls.
- Lovastatin-induced apoptosis was partially mediated by the mevalonate pathway.
- Caspase-2 and caspase-3 inhibitors significantly reduced lovastatin-induced apoptosis.
- Lovastatin-induced oncosis was mevalonate-independent and unaffected by caspase inhibitors.
Conclusions:
- Lovastatin induces complex cardiotoxicity through distinct apoptotic and oncotic cell death pathways.
- The apoptotic component is partly linked to the mevalonate pathway and modulated by caspase-2 and caspase-3.
- Oncosis occurs via a separate, mevalonate-independent mechanism.
- These findings highlight the multifaceted nature of lovastatin cardiotoxicity.
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