Minocycline protects cardiac myocytes against simulated ischemia–reperfusion injury by inhibiting poly(ADP-ribose) polymerase-1.
There is an increase in reactive oxygen and nitrogen species in cardiomyocytes during myocardial ischemia/reperfusion injury. This leads to oxidative DNA damage and activation of nuclear repair enzymes such as poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 activation promotes DNA repair under normal conditions. However, excessive activation of PARP-1 leads to cell death. We report that PARP-1 enzymatic activity is directly inhibited by minocycline, and we propose that one mechanism of minocycline cardioprotection is the result of PARP-1 inhibition. Using cultured adult rat cardiac myocytes, we evaluated the mechanism of minocycline protection in which PARP-1 activation was induced by simulated ischemia/reperfusion injury using oxygen–glucose deprivation.We found an increase in reactive oxygen species production, PARP-1 activation, and PARP-1-mediated cell death after simulated ischemia/reperfusion. Cell death was significantly reduced by the PARP inhibitors 3, 4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone (10 μM) and PJ-34 (500 nM) or by minocycline (500 nM). Cellular NAD(+) depletion and poly(ADP-ribose) formation, which are biochemical markers of PARP-1 activation, were also blocked by minocycline. Finally, simulated ischemia/reperfusion led to induction of the mitochondrial permeability transition, which was prevented by minocycline. Therefore, we propose that the protective effect of minocycline on cardiac myocyte survival is the result of inhibition of PARP-1 activity.
Tao
Rong
R
Cardiology Section, San Francisco VA Medical Center and UCSF, San Francisco, CA, USA.
Kim
Sun Hee
SH
Honbo
Norman
N
Karliner
Joel S
JS
Alano
Conrad C
CC
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008911:Minocycline / Q000494:pharmacology* / Q000627:therapeutic use; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D015427:Reperfusion Injury / Q000201:enzymology / Q000517:prevention & control*
D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D008911:Minocycline