Key result
Higher levels of heat shock protein 27 (HSP27) protected cardiac H9c2 cells and mouse fibroblasts against doxorubicin-induced toxicity by preserving aconitase activity.
HSP27 protects cardiac cells against doxorubicin-induced toxicity, likely by protecting aconitase from superoxide radicals via increased SOD activity.
Hypothesis-generating for HSP27 modulation in doxorubicin cardiotoxicity; clinical translation requires prospective human validation.
The use of doxorubicin (Dox) and its derivatives as chemotherapeutic drugs to treat patients with cancer causes dilated cardiomyopathy and congestive heart failure due to Dox-induced cardiotoxicity. In this work, using heat shock factor-1 wild-type (HSF-1(+/+)) and HSF-1 knockout (HSF-1(-/-)) mouse fibroblasts and embryonic rat heart-derived cardiac H9c2 cells, we show that the magnitude of protection from Dox-induced toxicity directly correlates with the level of the heat shock protein 27 (HSP27). Western blot analysis of normal and heat-shocked cells showed the maximum expression of HSP27 in heat-shocked cardiac H9c2 cells and no HSP27 in HSF-1(-/-) cells (normal or heat-shocked). Correspondingly, the cell viability, measured [with (3,4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay] after treatment with various concentrations of Dox, was the highest in heat-shocked H9c2 cells and the lowest in HSF-1(-/-) cells. Depleting HSP27 in cardiac H9c2 cells by small interfering (si)RNA also reduced the viability against Dox, confirming that HSP27 does protect cardiac cells against the Dox-induced toxicity. The cells that have lower HSP27 levels such as HSF-1(-/-), were found to be more susceptible for aconitase inactivation. Based on these results we propose a novel mechanism that HSP27 plays an important role in protecting aconitase from Dox-generated O(2)*(-), by increasing SOD activity. Such a protection of aconitase by HSP27 eliminates the catalytic recycling of aconitase released Fe(II) and its deleterious effects in cardiac cells.
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Turakhia et al. (2007) studied Doxorubicin-induced cardiotoxicity. Heat shock protein 27 (HSP27) vs. HSP27 depletion or HSF-1 knockout was evaluated on Cell viability and aconitase activity. Higher levels of heat shock protein 27 (HSP27) protected cardiac H9c2 cells and mouse fibroblasts against doxorubicin-induced toxicity by preserving aconitase activity.