Insulin-like growth factor binding protein-3 mediates serum starvation- and doxorubicin-induced apoptosis in H9c2 cardiac cells.
Insulin-like growth factor binding protein 3 (IGFBP-3) modulates the activity of IGF-I, which exerts antiapoptotic action upon the myocardiocyte. IGFBP-3 also exerts IGF-independent actions to inhibit cell growth and induce apoptosis, mediating the effects of several antiproliferative agents. We hypothesized that IGFBP-3 mediates cardiomyocyte apoptosis. IGFBP-3 expression was studied in H9c2 rat cardiac cells cultured in serum-deprived medium in the absence or presence of 1 microM doxorubicin during a 72 h time-span. To a greater degree than serum withdrawal, doxorubicin induced IGFBP-3 up-regulation that was time-dependent. IGFBP-3 mRNA levels positively correlated with the degree of apoptosis. Exogenous IGFBP-3 decreased cell viability and induced apoptosis in serum-starved cells exposed to doxorubicin. IGFBP-3 antisense oligonucleotides markedly decreased apoptosis induced by either serum withdrawal or doxorubicin. Binding studies revealed specific high-affinity sites for IGFBP-3 in H9c2 cardiomyocytes, with binding characteristics typical of receptor-ligand interactions. These findings indicate that IGFBP-3 could play proapoptotic action at the myocardial level and suggest a novel role for this protein in cardiovascular dysfunction.
Granata
R
R
Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Turin, Turin, Italy.
De Petrini
M
M
Trovato
L
L
Ponti
R
R
Pons
N
N
Ghè
C
C
Graziani
A
A
Ferry
R J
RJ
Muccioli
G
G
Ghigo
E
E
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D001665:Binding Sites; D001667:Binding, Competitive; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016895:Culture Media, Serum-Free / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D006321:Heart / Q000502:physiology*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D009206:Myocardium / Q000166:cytology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D051381:Rats
D016895:Culture Media, Serum-Free; D018972:Insulin-Like Growth Factor Binding Protein 3; D016376:Oligonucleotides, Antisense; D004317:Doxorubicin