The peroxynitrite decomposition catalyst FP15 improves ageing-associated cardiac and vascular dysfunction.
Overproduction of oxidants and free radicals in ageing tissues induces nitro-oxidative stress, which has recently been implicated in the pathogenesis of cardiovascular dysfunction associated with ageing. Peroxynitrite, a strong cytotoxic oxidant damages proteins and DNA and activates several pathways causing tissue injury, including the peroxynitrite-poly(ADP-ribose) polymerase (PARP) pathway. In this study, we investigated the effectiveness of the peroxynitrite decomposition catalyst FP15 on ageing-associated cardiac and vascular dysfunction. Young and ageing rats were treated with vehicle or FP15 intraperitoneally. Using a microtip Millar pressure catheter we performed left ventricular blood pressure analysis to assess systolic and diastolic function. Endothelium-dependent and -independent vasorelaxation of isolated aortic rings were investigated by using acetylcholine and sodium nitroprusside. Ageing animals showed a marked reduction of systolic and diastolic cardiac function and loss of endothelium-dependent relaxant responsiveness of aortic rings. FP15-treatment significantly improved cardiac performance and endothelial function. Immunohistochemical staining confirmed that FP15 effectively reduced nitrosative stress and prevented the activation of PARP in the aortic wall of ageing rats. Our results demonstrate the importance of endogenous peroxynitrite-overproduction in the pathogenesis of ageing-associated cardiovascular dysfunction. Pharmacological decomposition of peroxynitrite by FP15 may represent a novel therapeutic utility to improve cardiac and vascular dysfunction associated with ageing.
Radovits
Tamás
T
Department of Cardiac Surgery, University of Heidelberg, INF 326 OG 2, 69120 Heidelberg, Germany.
Seres
Leila
L
Gero
Domokos
D
Lin
Li-ni
LN
Beller
Carsten J
CJ
Chen
Song-He
SH
Zotkina
Julia
J
Berger
Irina
I
Groves
John T
JT
Szabó
Csaba
C
Szabó
Gábor
G
D000109:Acetylcholine / Q000494:pharmacology; D000375:Aging / Q000187:drug effects*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D003971:Diastole / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D006331:Heart Diseases / Q000188:drug therapy*; D066298:In Vitro Techniques; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014443:Tyrosine / Q000031:analogs & derivatives / Q000276:immunology / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
C471469:FeCl tetrakis-2-(triethyleneglycolmonomethylether)pyridylporphyrin; D008665:Metalloporphyrins; C002744:3-nitrotyrosine; D014443:Tyrosine; D052250:Nitric Oxide Synthase Type III; D011065:Poly(ADP-ribose) Polymerases; D000109:Acetylcholine