Inhibition of matrix metalloproteinase-2 by PARP inhibitors.
Matrix metalloproteinase-2 (MMP-2), a ubiquitously expressed zinc-dependent endopeptidase, and poly(ADP-ribosyl) polymerase (PARP), a nuclear enzyme regulating DNA repair, are activated by nitroxidative stress associated with various pathologies. As MMP-2 plays a detrimental role in heart injuries resulting from enhanced nitroxidative stress, where PARP and MMP inhibitors are beneficial, we hypothesized that PARP inhibitors may affect MMP-2 activity. Using substrate degradation assays to determine MMP-2 activity we found that four PARP inhibitors (3-AB, PJ-34, 5-AIQ, and EB-47) inhibited 64kDa MMP-2 in a concentration-dependent manner. The IC(50) values of PJ-34 and 5-AIQ were in the high micromolar range and comparable to those of known MMP-2 inhibitors doxycycline, minocycline or o-phenanthroline, whereas those for 3-AB and EB-47 were in the millimolar range. Co-incubation of PARP inhibitors with doxycycline showed an additive inhibition of MMP-2 that was significant for 3-AB alone. These data demonstrate that the protective effects of some PARP inhibitors may include inhibition of MMP-2 activity.
Nicolescu
Adrian C
AC
Departments of Pharmacology and Pediatrics, Cardiovascular Research Centre, University of Alberta, Edmonton, Alta., Canada.
Holt
Andrew
A
Kandasamy
Arulmozhi D
AD
Pacher
Pal
P
Schulz
Richard
R
D001549:Benzamides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000494:pharmacology; D061965:Matrix Metalloproteinase Inhibitors; D010616:Phenanthrenes / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D015032:Zinc / Q000494:pharmacology
C411425:5-aminoisoquinolinone; D001549:Benzamides; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D061965:Matrix Metalloproteinase Inhibitors; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C025160:3-aminobenzamide; D015032:Zinc