Abstract
Doxorubicin (DOX) and its derivatives are used as chemotherapeutic drugs to treat cancer patients. However, production of DOX-mediated reactive oxygen species (ROS) by prolonged use of these drugs has been found to cause dilative cardiomyopathy and congestive heart failure. Thus various preventive modalities have been developed to avoid this side effect. We have found that the DOX-mediated oxidant-induced toxicity in cardiac cells could be minimized by hyperthermia-induced small heat shock protein 27 (HSP27); that is, this protein acts as an endogenous antioxidant against DOX-derived oxidants such as H 2O2. Heat shock-induced HSP27 was found to act as an antiapoptotic protein (reducing ROS and Bax-to-Bcl2 ratio) against DOX, and its phosphorylated isoforms stabilized F-actin remodeling in DOX-treated cardiac cells and, hence, attenuated the toxicity. Protein kinase assays and proteomic analyses suggested that higher expression of HSP27 and its phosphorylation are responsible for the protection in heat-shocked cells. Two-dimensional gel electrophoresis showed six isoforms (non-phosphorylated and phosphorylated) of HSP27. Matrix-assisted laser desorption/ionization time of flight analyses showed α- and β-isoforms of HSP27, which are phosphorylated by various protein kinases. Ser15 and Ser85 phosphorylation of HSP27 by MAPK-assisted protein kinase 2 was found to be the key mechanism in reduction of apoptosis and facilitation of F-actin remodeling. The present study illustrates that hyperthermia protects cells from DOX-induced death through induction and phosphorylation of HSP27 and its antiapoptotic and actin-remodeling activities.
| Original language | English (US) |
|---|---|
| Journal | American Journal of Physiology - Heart and Circulatory Physiology |
| Volume | 291 |
| Issue number | 6 |
| DOIs | |
| State | Published - 2006 |
| Externally published | Yes |
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Keywords
- Apoptosis
- Cardiomyopathy
- Hyperthermia
ASJC Scopus subject areas
- Physiology
Cite this
Heat shock protects cardiac cells from doxorubicin-induced toxicity by activating p38 MAPK and phosphorylation of small heat shock protein 27. / Venkatakrishnan, C. D.; Tewari, Arun K.; Moldovan, Leni; Cardounel, Arturo J.; Zweier, Jay L.; Kuppusamy, Periannan; Ilangovan, Govindasamy.
In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 291, No. 6, 2006.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Heat shock protects cardiac cells from doxorubicin-induced toxicity by activating p38 MAPK and phosphorylation of small heat shock protein 27
AU - Venkatakrishnan, C. D.
AU - Tewari, Arun K.
AU - Moldovan, Leni
AU - Cardounel, Arturo J.
AU - Zweier, Jay L.
AU - Kuppusamy, Periannan
AU - Ilangovan, Govindasamy
PY - 2006
Y1 - 2006
N2 - Doxorubicin (DOX) and its derivatives are used as chemotherapeutic drugs to treat cancer patients. However, production of DOX-mediated reactive oxygen species (ROS) by prolonged use of these drugs has been found to cause dilative cardiomyopathy and congestive heart failure. Thus various preventive modalities have been developed to avoid this side effect. We have found that the DOX-mediated oxidant-induced toxicity in cardiac cells could be minimized by hyperthermia-induced small heat shock protein 27 (HSP27); that is, this protein acts as an endogenous antioxidant against DOX-derived oxidants such as H 2O2. Heat shock-induced HSP27 was found to act as an antiapoptotic protein (reducing ROS and Bax-to-Bcl2 ratio) against DOX, and its phosphorylated isoforms stabilized F-actin remodeling in DOX-treated cardiac cells and, hence, attenuated the toxicity. Protein kinase assays and proteomic analyses suggested that higher expression of HSP27 and its phosphorylation are responsible for the protection in heat-shocked cells. Two-dimensional gel electrophoresis showed six isoforms (non-phosphorylated and phosphorylated) of HSP27. Matrix-assisted laser desorption/ionization time of flight analyses showed α- and β-isoforms of HSP27, which are phosphorylated by various protein kinases. Ser15 and Ser85 phosphorylation of HSP27 by MAPK-assisted protein kinase 2 was found to be the key mechanism in reduction of apoptosis and facilitation of F-actin remodeling. The present study illustrates that hyperthermia protects cells from DOX-induced death through induction and phosphorylation of HSP27 and its antiapoptotic and actin-remodeling activities.
AB - Doxorubicin (DOX) and its derivatives are used as chemotherapeutic drugs to treat cancer patients. However, production of DOX-mediated reactive oxygen species (ROS) by prolonged use of these drugs has been found to cause dilative cardiomyopathy and congestive heart failure. Thus various preventive modalities have been developed to avoid this side effect. We have found that the DOX-mediated oxidant-induced toxicity in cardiac cells could be minimized by hyperthermia-induced small heat shock protein 27 (HSP27); that is, this protein acts as an endogenous antioxidant against DOX-derived oxidants such as H 2O2. Heat shock-induced HSP27 was found to act as an antiapoptotic protein (reducing ROS and Bax-to-Bcl2 ratio) against DOX, and its phosphorylated isoforms stabilized F-actin remodeling in DOX-treated cardiac cells and, hence, attenuated the toxicity. Protein kinase assays and proteomic analyses suggested that higher expression of HSP27 and its phosphorylation are responsible for the protection in heat-shocked cells. Two-dimensional gel electrophoresis showed six isoforms (non-phosphorylated and phosphorylated) of HSP27. Matrix-assisted laser desorption/ionization time of flight analyses showed α- and β-isoforms of HSP27, which are phosphorylated by various protein kinases. Ser15 and Ser85 phosphorylation of HSP27 by MAPK-assisted protein kinase 2 was found to be the key mechanism in reduction of apoptosis and facilitation of F-actin remodeling. The present study illustrates that hyperthermia protects cells from DOX-induced death through induction and phosphorylation of HSP27 and its antiapoptotic and actin-remodeling activities.
KW - Apoptosis
KW - Cardiomyopathy
KW - Hyperthermia
UR - http://www.scopus.com/inward/record.url?scp=33845467937&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33845467937&partnerID=8YFLogxK
U2 - 10.1152/ajpheart.00395.2006
DO - 10.1152/ajpheart.00395.2006
M3 - Article
C2 - 16782845
AN - SCOPUS:33845467937
VL - 291
JO - American Journal of Physiology
JF - American Journal of Physiology
SN - 0363-6135
IS - 6
ER -