[Novel antioxidant therapeutic strategies for cardiovascular dysfunction associated with ageing].
Overproduction of free radicals in ageing tissues induces nitro-oxidative stress, which has been implicated in the functional decline of the cardiovascular system at old age. Toxic oxidants like hydrogen peroxide or peroxynitrite damage proteins and DNA and activate several pathways causing tissue injury, including the poly(ADP-ribose) polymerase (PARP) pathway.


OBJECTIVE
First, we tested whether the inhibition of PARP can improve endothelial dysfunction induced by hydrogen peroxide in an in vitro model of vascular oxidative stress. In turn, our main aim was to investigate the effects of acute PARP inhibition and catalytic peroxynitrite decomposition on ageing-associated cardiac and endothelial dysfunction.


METHODS
In vascular reactivity measurements on isolated rat aortic rings, we investigated the endothelium-dependent and -independent vasorelaxation by using acetylcholine and sodium nitroprusside. Endothelial dysfunction was induced by hydrogen peroxide. In the treatment group, rings were preincubated with a PARP-inhibitor. In the in vivo rat model of ageing-associated cardiovascular dysfunction, young and ageing rats were treated with a single dose of PARP-inhibitor, or with the peroxynitrite decomposition catalyst FP15. Using a pressure-conductance catheter, left ventricular pressure-volume analysis was performed to study cardiac function. Endothelium-dependent and -independent relaxation of aortic rings were investigated. Immunohistochemical analysis was performed to study the changes on the cellular and tissue level.


RESULTS
In our in vitro model, hydrogen peroxide caused a dose-dependent impairment of endothelium-dependent vasorelaxation of aortic rings which was significantly improved by PARP-inhibition. Ageing rats showed a marked reduction of cardiac function and loss of endothelium-dependent relaxant responsiveness of aortic rings. Both acute PARP-inhibition and FP15-treatment improved cardiac performance and endothelial function. Immunohistochemistry confirmed enhanced nitro-oxidative stress and PARP-activation in ageing rats, which were reversed in the treatment groups.


CONCLUSIONS
Our results demonstrate the importance of endogenous peroxynitrite-overproduction and the activation of the PARP pathway in the age-related functional decline of the cardiovascular system. Catalytic peroxynitrite decomposition and PARP-inhibition may represent novel antioxidant therapeutic utilities to improve ageing-associated cardiovascular dysfunction.
Radovits
Tamás
T
Ruprecht-Karls Egyetem Szívsebészeti Klinika, Kísérleti Kutató Laboratórium Heidelberg Németország Semmelweis Egyetem, Altalános Orvostudományi Kar Kardiológiai Központ Budapest. radovitstamas@yahoo.com
D000375:Aging; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D001011:Aorta / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005609:Free Radicals / Q000009:adverse effects; D006861:Hydrogen Peroxide / Q000009:adverse effects; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D018384:Oxidative Stress / Q000187:drug effects; D030421:Peroxynitrous Acid / Q000009:adverse effects* / Q000096:biosynthesis / Q000378:metabolism*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D015854:Up-Regulation; D014664:Vasodilation / Q000187:drug effects*; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects
D000975:Antioxidants; D005609:Free Radicals; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D030421:Peroxynitrous Acid; D006861:Hydrogen Peroxide; D011065:Poly(ADP-ribose) Polymerases