Expression of p300 protects cardiac myocytes from apoptosis in vivo

Teruhisa Kawamura; Koji Hasegawa; Tatsuya Morimoto; Eri Iwai-Kanai; Shoichi Miyamoto; Yosuke Kawase; Koh Ono; Hiromichi Wada; Masaharu Akao; Toru Kita

doi:10.1016/j.bbrc.2004.01.105

Expression of p300 protects cardiac myocytes from apoptosis in vivo

Biochem Biophys Res Commun. 2004 Mar 12;315(3):733-8. doi: 10.1016/j.bbrc.2004.01.105.

Authors

Teruhisa Kawamura¹, Koji Hasegawa, Tatsuya Morimoto, Eri Iwai-Kanai, Shoichi Miyamoto, Yosuke Kawase, Koh Ono, Hiromichi Wada, Masaharu Akao, Toru Kita

Affiliation

¹ Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.

PMID: 14975762
DOI: 10.1016/j.bbrc.2004.01.105

Abstract

Doxorubicin is an anti-tumor agent that represses cardiac-specific gene expression and induces myocardial cell apoptosis. Doxorubicin depletes cardiac p300, a transcriptional coactivator that is required for the maintenance of the differentiated phenotype of cardiac myocytes. However, the role of p300 in protection against doxorubicin-induced apoptosis is unknown. Transgenic mice overexpressing p300 in the heart and wild-type mice were subjected to doxorubicin treatment. Compared with wild-type mice, transgenic mice exhibited higher survival rate as well as more preserved left ventricular function and cardiac expression of alpha-sarcomeric actin. Doxorubicin induced myocardial cell apoptosis in wild-type mice but not in transgenic mice. Expression of p300 increased the cardiac level of bcl-2 and mdm-2, but not that of p53 or other members of the bcl-2 family. These findings demonstrate that overexpression of p300 protects cardiac myocytes from doxorubicin-induced apoptosis and reduces the extent of acute heart failure in adult mice in vivo.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Actins / biosynthesis
Animals
Antineoplastic Agents / toxicity
Apoptosis / drug effects
Apoptosis / physiology*
Caspase 3
Caspases / metabolism
Doxorubicin / antagonists & inhibitors
Doxorubicin / toxicity*
E1A-Associated p300 Protein
Gene Expression
Heart Failure / chemically induced
Heart Failure / metabolism
Heart Failure / prevention & control
Mice
Mice, Transgenic
Myocardium / metabolism
Myocytes, Cardiac / cytology*
Myocytes, Cardiac / drug effects
Myocytes, Cardiac / metabolism*
Nuclear Proteins / biosynthesis
Nuclear Proteins / genetics
Nuclear Proteins / physiology*
Proto-Oncogene Proteins / biosynthesis
Proto-Oncogene Proteins c-bcl-2 / biosynthesis
Proto-Oncogene Proteins c-mdm2
RNA, Messenger / biosynthesis
Sarcomeres / metabolism
Trans-Activators / biosynthesis
Trans-Activators / genetics
Trans-Activators / physiology*
Ventricular Function, Left / drug effects
Ventricular Function, Left / physiology

Substances

Actins
Antineoplastic Agents
Nuclear Proteins
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-bcl-2
RNA, Messenger
Trans-Activators
Doxorubicin
E1A-Associated p300 Protein
Ep300 protein, mouse
Mdm2 protein, mouse
Proto-Oncogene Proteins c-mdm2
Casp3 protein, mouse
Caspase 3
Caspases