Poli(ADP-ribóz) polimeráz gátló vegyületek hatásmechanizmusának vizsgálata állatkísérletes és rheologiai modelleken = Evaluation of mechanism of action of poly(ADP-ribose) polymerase inhibitor compounds in animal and in rheological models

Kutatasaink soran kiserletes szivelegtelenseg modellekben vizsgalatuk a poli(ADP-riboz) polimeraz (PARP) gatlok hatasat. Vizsgalatainkkal igazoltuk, hogy PARP-gatlok merseklik a postinfarctusos remodelinget es vedenek a szivelegtelenseg kialakulasaval szemben. Elsőkent igazoltuk, hogy a PARP-gatlok jelentős hatassal birnak a szivelegtelenseg pathomechanizmusaban alapvető szerepet jatszo jelatviteli utakra is. PARP-gatlas fokozta a tulelest segitő, ugyanakkor csokkentette bizonyos maladaptiv jelatviteli utak aktivitasat. Mindezek kovetkezteben a PARP-gatloval kezelt szivek mind funkcionalisan, mind strukturalisan lenyegesen intaktabbak voltak, mint a kezeletlen szivek. Raadasul az ACE-gatlo enalaprillal osszehasonitva a PARP-gatlo kezeles hatekonyabbnak bizonyult a myocardialis remodeling kivedeseben postinfarktusos szivelegtelenseg modellben. Fiatal spontan hipertenziv patkanyokban a PARP-gatloknak a szivizom hypertrophia kialakulasaval szembeni vedő hatasat igazoltuk. Ezen eredmenyeink publikalasra kerultek mar, illetve egyesek meg publikalas alatt allnak. Emellett idős spontan hipertenziv patkanyokban a pangasos szivelegtelenseg kialakulasaval szemben is kifejezett vedő hatast mutattak a PARP-gatlok, az allatok tuleleset is javitotta a kezeles. Ezen adatain meg reszben feldolgozasra varnak. Doxorubicin kezeles altal kivaltott cardiomyopathia modellben vegzett vizsgalatunkbol szarmazo mintak meg feldolgozas alatt allnak. | The effect of poly(ADP-ribose) polymerase (PARP) inhibitors was studied in various experimental heart failure models. We have demonstrated that PARP-inhibitors can moderate the postinfarction myocardial remodeling and can protect against the development of heart failure. We have firstly proved that PARP-inhibitors have a significant effect on signal transduction pathways which play a central role in the development of heart failure. PARP-inhibition activated the prosurvival signal transduction pathways and blocked the activity of several maladaptive signal transduction pathways. Due to these effects, hearts treated with PARP-inhibitors showed better functional and structural features compared to untreated hearts. In addition, PARP-inhibition was more effective against the development of myocardial remodeling in our postinfarction heart failure model compared to ACE-inhibition. In young spontaneous hypertensive rats the protective effect of PARP-inhibitors against the development of myocardial hypertrophy was demonstrated. These results were already published and several data are under publication. Moreover, in adult spontaneous hypertensive rats PARP-inhibition protects against the transition from hypertrophic cardiomyopathy to decompensated heart failure. These results will be published shortly. Finally, tissue samples derived from a toxic (doxorubicin-induced) cardiomyopathy model are yet under measurements.