Faculty Collaboration Database

Differences in doxorubicin-induced apoptotic signaling in adult and immature cardiomyocytes. Free Radic Biol Med 2008 Dec 15;45(12):1723-8

Date

10/18/2008

Pubmed ID

18926904

Pubmed Central ID

PMC3039518

DOI

10.1016/j.freeradbiomed.2008.09.006

Scopus ID

2-s2.0-56349128620 (requires institutional sign-in at Scopus site)   55 Citations

Abstract

A proposed mechanism for the cardiotoxicity of doxorubicin (DOX) involves apoptosis in cardiomyocytes. In the study described here, we investigated the molecular basis for the differences in DOX-induced toxicity in adult rat cardiomyocytes (ARCM), neonatal rat cardiomyocytes (NRCM), and rat embryonic H9c2 cardiomyoblasts. Activation of caspase-9 and -3 was considerably lower in DOX-treated ARCM as compared with NRCM and H9c2 cardiomyoblasts. Addition of cytochrome c caused the activation of caspase-9 and -3 in permeabilized NRCM and H9c2 cardiomyoblasts but not in permeabilized ARCM. Expression of proapoptotic proteins, apoptotic protease activating factor-1 (Apaf1), and procaspase-9 was significantly lower, and abundance of antiapoptotic X-linked inhibitor of apoptosis protein (XIAP) was higher in ARCM, as compared with immature cardiac cells. Despite the abundance of XIAP in ARCM, its role in the inhibition of apoptosome function was dismissed, as second mitochondria-derived activator of caspases (Smac)-N7 peptide, had no effect on caspase activation in response to cytochrome c in these cells. Adenoviral expression of Apaf1 exacerbated the activation of caspase-9 and -3 in DOX-treated NRCM, but did not increase their activities in DOX-treated ARCM. This finding points to a major difference in the apoptotic signaling between immature and adult cardiomyocytes. The mitochondrial apoptotic pathway is limited in ARCM treated with DOX.

Author List

Konorev EA, Vanamala S, Kalyanaraman B

Author

Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenoviridae
Animals
Animals, Newborn
Antibiotics, Antineoplastic
Apoptosis
Apoptosis Regulatory Proteins
Apoptosomes
Apoptotic Protease-Activating Factor 1
Carrier Proteins
Caspases
Cytochromes c
Doxorubicin
Enzyme Activation
Immunoblotting
Male
Mitochondrial Proteins
Myoblasts, Cardiac
Myocytes, Cardiac
Rats
Rats, Sprague-Dawley
Signal Transduction
Subcellular Fractions
X-Linked Inhibitor of Apoptosis Protein