Downregulation of doxorubicin-induced myocardial apoptosis accompanies postnatal heart maturation

Jianjian Shi, Lumin Zhang, Yi Wei Zhang, Michelle Surma, R. Payne, Lei Wei

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Doxorubicin is a highly effective chemotherapeutic agent used for treating a wide spectrum of tumors, but its usage is limited because of its dose-dependent cardiotoxicity, especially in pediatric patients. Accumulating evidence indicates that caspase-dependent apoptosis contributes to the cardiotoxicity of doxorubicin. However, less attention has been paid to the effects of age on doxorubicin-induced apoptosis signaling in myocardium. This study focused on investigating differential apoptotic sensitivity between neonatal and adult myocardium, in particular, between neonatal and adult cardiomyocytes in vivo. Our results show that caspase-3 activity in normal mouse hearts decreased by ≥20-fold within the first 3 wk after birth, associated with a rapid downregulation in the expression of key proapoptotic proteins in intrinsic and extrinsic pathways. This rapid downregulation of caspase-3 activity was confirmed by immunostaining for cleaved caspase-3 and terminal deoxynucleotidyl transferase dUTP-mediated nick-end label staining. Doxorubicin treatment induced a dose-dependent increase in caspase-3 activity and apoptosis in neonatal mouse hearts, and both caspase-8 and caspase-9 activations were involved. Using transgenic mice with a nuclear localized LacZ reporter gene to label cardiomyocytes in vivo, we observed a fourfold higher level of doxorubicininduced cardiomyocyte apoptosis in 1-wk-old mice compared with that in 3-wk-old mice. This study points to a major difference in apoptotic signaling in doxorubicin cardiotoxicity between neonatal and adult mouse hearts and reveals a critical transition from high to low susceptibility to doxorubicin-induced apoptosis during postnatal heart maturation.

Original languageEnglish
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume302
Issue number8
DOIs
StatePublished - Apr 15 2012

Fingerprint

Doxorubicin
Down-Regulation
Apoptosis
Caspase 3
Cardiac Myocytes
Myocardium
Lac Operon
DNA Nucleotidylexotransferase
Caspase 9
Caspase 8
Caspases
Reporter Genes
Transgenic Mice
Parturition
Pediatrics
Staining and Labeling
Cardiotoxicity
Neoplasms
Proteins

Keywords

  • Anthracycline
  • Cardiomyocyte
  • Cardiotoxicity
  • Caspase
  • Chemotherapy

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Downregulation of doxorubicin-induced myocardial apoptosis accompanies postnatal heart maturation. / Shi, Jianjian; Zhang, Lumin; Zhang, Yi Wei; Surma, Michelle; Payne, R.; Wei, Lei.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 302, No. 8, 15.04.2012.

Research output: Contribution to journalArticle

@article{aac48859cd264e4b9f0a18c0dde1137e,
title = "Downregulation of doxorubicin-induced myocardial apoptosis accompanies postnatal heart maturation",
abstract = "Doxorubicin is a highly effective chemotherapeutic agent used for treating a wide spectrum of tumors, but its usage is limited because of its dose-dependent cardiotoxicity, especially in pediatric patients. Accumulating evidence indicates that caspase-dependent apoptosis contributes to the cardiotoxicity of doxorubicin. However, less attention has been paid to the effects of age on doxorubicin-induced apoptosis signaling in myocardium. This study focused on investigating differential apoptotic sensitivity between neonatal and adult myocardium, in particular, between neonatal and adult cardiomyocytes in vivo. Our results show that caspase-3 activity in normal mouse hearts decreased by ≥20-fold within the first 3 wk after birth, associated with a rapid downregulation in the expression of key proapoptotic proteins in intrinsic and extrinsic pathways. This rapid downregulation of caspase-3 activity was confirmed by immunostaining for cleaved caspase-3 and terminal deoxynucleotidyl transferase dUTP-mediated nick-end label staining. Doxorubicin treatment induced a dose-dependent increase in caspase-3 activity and apoptosis in neonatal mouse hearts, and both caspase-8 and caspase-9 activations were involved. Using transgenic mice with a nuclear localized LacZ reporter gene to label cardiomyocytes in vivo, we observed a fourfold higher level of doxorubicininduced cardiomyocyte apoptosis in 1-wk-old mice compared with that in 3-wk-old mice. This study points to a major difference in apoptotic signaling in doxorubicin cardiotoxicity between neonatal and adult mouse hearts and reveals a critical transition from high to low susceptibility to doxorubicin-induced apoptosis during postnatal heart maturation.",
keywords = "Anthracycline, Cardiomyocyte, Cardiotoxicity, Caspase, Chemotherapy",
author = "Jianjian Shi and Lumin Zhang and Zhang, {Yi Wei} and Michelle Surma and R. Payne and Lei Wei",
year = "2012",
month = "4",
day = "15",
doi = "10.1152/ajpheart.00844.2011",
language = "English",
volume = "302",
journal = "American Journal of Physiology",
issn = "0193-1857",
publisher = "American Physiological Society",
number = "8",

}

TY - JOUR

T1 - Downregulation of doxorubicin-induced myocardial apoptosis accompanies postnatal heart maturation

AU - Shi, Jianjian

AU - Zhang, Lumin

AU - Zhang, Yi Wei

AU - Surma, Michelle

AU - Payne, R.

AU - Wei, Lei

PY - 2012/4/15

Y1 - 2012/4/15

N2 - Doxorubicin is a highly effective chemotherapeutic agent used for treating a wide spectrum of tumors, but its usage is limited because of its dose-dependent cardiotoxicity, especially in pediatric patients. Accumulating evidence indicates that caspase-dependent apoptosis contributes to the cardiotoxicity of doxorubicin. However, less attention has been paid to the effects of age on doxorubicin-induced apoptosis signaling in myocardium. This study focused on investigating differential apoptotic sensitivity between neonatal and adult myocardium, in particular, between neonatal and adult cardiomyocytes in vivo. Our results show that caspase-3 activity in normal mouse hearts decreased by ≥20-fold within the first 3 wk after birth, associated with a rapid downregulation in the expression of key proapoptotic proteins in intrinsic and extrinsic pathways. This rapid downregulation of caspase-3 activity was confirmed by immunostaining for cleaved caspase-3 and terminal deoxynucleotidyl transferase dUTP-mediated nick-end label staining. Doxorubicin treatment induced a dose-dependent increase in caspase-3 activity and apoptosis in neonatal mouse hearts, and both caspase-8 and caspase-9 activations were involved. Using transgenic mice with a nuclear localized LacZ reporter gene to label cardiomyocytes in vivo, we observed a fourfold higher level of doxorubicininduced cardiomyocyte apoptosis in 1-wk-old mice compared with that in 3-wk-old mice. This study points to a major difference in apoptotic signaling in doxorubicin cardiotoxicity between neonatal and adult mouse hearts and reveals a critical transition from high to low susceptibility to doxorubicin-induced apoptosis during postnatal heart maturation.

AB - Doxorubicin is a highly effective chemotherapeutic agent used for treating a wide spectrum of tumors, but its usage is limited because of its dose-dependent cardiotoxicity, especially in pediatric patients. Accumulating evidence indicates that caspase-dependent apoptosis contributes to the cardiotoxicity of doxorubicin. However, less attention has been paid to the effects of age on doxorubicin-induced apoptosis signaling in myocardium. This study focused on investigating differential apoptotic sensitivity between neonatal and adult myocardium, in particular, between neonatal and adult cardiomyocytes in vivo. Our results show that caspase-3 activity in normal mouse hearts decreased by ≥20-fold within the first 3 wk after birth, associated with a rapid downregulation in the expression of key proapoptotic proteins in intrinsic and extrinsic pathways. This rapid downregulation of caspase-3 activity was confirmed by immunostaining for cleaved caspase-3 and terminal deoxynucleotidyl transferase dUTP-mediated nick-end label staining. Doxorubicin treatment induced a dose-dependent increase in caspase-3 activity and apoptosis in neonatal mouse hearts, and both caspase-8 and caspase-9 activations were involved. Using transgenic mice with a nuclear localized LacZ reporter gene to label cardiomyocytes in vivo, we observed a fourfold higher level of doxorubicininduced cardiomyocyte apoptosis in 1-wk-old mice compared with that in 3-wk-old mice. This study points to a major difference in apoptotic signaling in doxorubicin cardiotoxicity between neonatal and adult mouse hearts and reveals a critical transition from high to low susceptibility to doxorubicin-induced apoptosis during postnatal heart maturation.

KW - Anthracycline

KW - Cardiomyocyte

KW - Cardiotoxicity

KW - Caspase

KW - Chemotherapy

UR - http://www.scopus.com/inward/record.url?scp=84859744074&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84859744074&partnerID=8YFLogxK

U2 - 10.1152/ajpheart.00844.2011

DO - 10.1152/ajpheart.00844.2011

M3 - Article

C2 - 22328080

AN - SCOPUS:84859744074

VL - 302

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 0193-1857

IS - 8

ER -