INO-4885 [5,10,15,20-tetra[N-(benzyl-4'-carboxylate)-2-pyridinium]-21H,23H-porphine iron(III) chloride], a peroxynitrite decomposition catalyst, protects the heart against reperfusion injury in mice.
Oxidative/nitrative stress caused by peroxynitrite, the reaction product of superoxide (O2(.-)) and nitric oxide (NO), is the primary cause of myocardial ischemia/reperfusion injury. The present study determined whether INO-4885 [5,10,15,20-tetra[N-(benzyl-4'-carboxylate)-2-pyridinium]-21H,23H-porphine iron(III) chloride], a new peroxynitrite decomposition catalyst, may provide cellular protection and protect heart from myocardial ischemia/reperfusion injury. Adult male mice were subjected to 30 min of ischemia and 3 or 24 h of reperfusion. Mice were randomized to receive vehicle, INO-4885 without catalytic moiety, or INO-4885 (3-300 microg/kg i.p.) 10 min before reperfusion. Infarct size, apoptosis, nitrotyrosine content, NO/O2(.-) production, and inducible nitric-oxide synthase (iNOS)/NADPH oxidase expression were determined. INO-4885 treatment reduced ischemia/reperfusion-induced protein nitration and caspase 3 activation in a dose-dependent fashion in the range of 3 to 100 microg/kg. However, doses exceeding 100 microg/kg produced nonspecific effects and attenuated its protective ability. At the optimal dose (30 microg/kg), INO-4885 significantly reduced infarct size (p < 0.01), decreased apoptosis (p < 0.01), and reduced tissue nitrotyrosine content (p < 0.01). As expected, INO-4885 had no effect on ischemia/reperfusion-induced iNOS expression and NO overproduction. To our surprise, this compound significantly reduced superoxide production and partially blocked NADPH oxidase overexpression in the ischemic/reperfused cardiac tissue. Additional experiments demonstrated that INO-4885 provided better cardioprotection than N-(3-(aminomethyl)benzyl)acetamidine (1400W, a selective iNOS inhibitor), apocynin (an NADPH oxidase inhibitor), or Tiron (a cell-permeable superoxide scavenger). Taken together, our data demonstrated that INO-4885 is a cardioprotective molecule that attenuates myocardial reperfusion injury by facilitating peroxynitrite decomposition and inhibiting NADPH oxidase-derived O2(.-) production.
Jiao
Xiang-Ying
XY
Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Gao
Erhe
E
Yuan
Yuexin
Y
Wang
Yajing
Y
Lau
Wayne Bond
WB
Koch
Walter
W
Ma
Xin-Liang
XL
Tao
Ling
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D006321:Heart / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D008297:Male; D008665:Metalloporphyrins / Q000627:therapeutic use*; D051379:Mice; D009203:Myocardial Infarction / Q000517:prevention & control*; D019255:NADPH Oxidases / Q000187:drug effects / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D030421:Peroxynitrous Acid / Q000627:therapeutic use*; D015427:Reperfusion Injury / Q000517:prevention & control*
C539253:(5,10,15,20-tetrakis(N-(benzyl-4'-carboxylate)-2-pyridinium)-21H,23H-porphine)iron(III); D008665:Metalloporphyrins; D030421:Peroxynitrous Acid; D052247:Nitric Oxide Synthase Type II; D019255:NADPH Oxidases; D053148:Caspase 3