Protective effects of the PARP-1 inhibitor PJ34 in hypoxic-reoxygenated cardiomyoblasts.
To clarify the role of poly(ADP-ribose)polymerase-1 (PARP-1) in myocardial ischemia-reperfusion injury, we explored some effects of PJ34, a highly specific inhibitor of this enzyme, in hypoxic-reoxygenated (HR) H9c2 cardiomyoblasts. Compared to the control, HR cells showed signs of oxidative stress, marked PARP-1 activation, NAD(+) and ATP depletion and impaired mitochondrial activity. HR cardiomyoblasts were affected by both necrosis and apoptosis, the latter involving the nuclear translocation of apoptosis-inducing factor. In HR cardiomyoblasts treated with PJ34, oxidative stress and PARP-1 activity were decreased, and NAD(+) and ATP depletion, as well as mitochondrial impairment, were attenuated. Above all, PJ34 treatment improved the survival of HR cells; not only was necrosis significantly diminished, but apoptosis was also reduced and shifted from a caspase-independent to a caspase-dependent pathway. These results suggest that PARP-1 modulation by a selective inhibitor such as PJ34 may represent a promising approach to limit myocardial damage due to post-ischemic reperfusion.
Fiorillo
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Dipartimento di Scienze Biochimiche, Università di Firenze, Viale Morgagni 50, 50134, Firenze, Italy. claudia.fiorillo@unifi.it
Ponziani
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V
Giannini
L
L
Cecchi
C
C
Celli
A
A
Nassi
N
N
Lanzilao
L
L
Caporale
R
R
Nassi
P
P
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015687:Cell Hypoxia; D002460:Cell Line; D002470:Cell Survival; D004396:Coloring Agents / Q000494:pharmacology; D032386:Myoblasts, Cardiac / Q000187:drug effects*; D009243:NAD / Q000378:metabolism; D009336:Necrosis; D018384:Oxidative Stress; D010616:Phenanthrenes / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
D004396:Coloring Agents; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts; D013844:Thiazoles; D009243:NAD; D000255:Adenosine Triphosphate; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; C022616:thiazolyl blue