Abstract
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.
| Original language | English (US) |
|---|---|
| Journal | American Journal of Physiology - Heart and Circulatory Physiology |
| Volume | 293 |
| Issue number | 5 |
| DOIs | |
| State | Published - Nov 2007 |
| Externally published | Yes |
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Keywords
- Superoxide dismutase
ASJC Scopus subject areas
- Physiology
Cite this
Doxorubicin-induced cardiotoxicity : Direct correlation of cardiac fibroblast and H9c2 cell survival and aconitase activity with heat shock protein 27. / Turakhia, Samir; Venkatakrishnan, C. D.; Dunsmore, Kathy; Wong, Hector; Kuppusamy, Periannan; Zweier, Jay L.; Ilangovan, Govindasamy.
In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 293, No. 5, 11.2007.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Doxorubicin-induced cardiotoxicity
T2 - Direct correlation of cardiac fibroblast and H9c2 cell survival and aconitase activity with heat shock protein 27
AU - Turakhia, Samir
AU - Venkatakrishnan, C. D.
AU - Dunsmore, Kathy
AU - Wong, Hector
AU - Kuppusamy, Periannan
AU - Zweier, Jay L.
AU - Ilangovan, Govindasamy
PY - 2007/11
Y1 - 2007/11
N2 - 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.
AB - 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.
KW - Superoxide dismutase
UR - http://www.scopus.com/inward/record.url?scp=36148985677&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=36148985677&partnerID=8YFLogxK
U2 - 10.1152/ajpheart.00328.2007
DO - 10.1152/ajpheart.00328.2007
M3 - Article
VL - 293
JO - American Journal of Physiology
JF - American Journal of Physiology
SN - 0363-6135
IS - 5
ER -