title: Enalaprilat increases PPARβ/δ expression, without influence on PPARα and PPARγ, and modulate cardiac function in sub-acute model of daunorubicin-induced cardiomyopathy.
abstract: Anthracycline therapy is limited by a cardiotoxicity that may eventually lead to chronic heart failure which is thought to be prevented by ACE inhibitors (ACEi). However, the protective effect of ACEi in early stages of this specific injury remains elusive. Activated nuclear transcription factors peroxisome proliferator-activated receptors (PPAR) regulate cellular metabolism, but their involvement in anthracycline cardiomyopathy has not been investigated yet. For this purpose, Wistar rats were administered with daunorubicin (i.p., 3 mg/kg, in 48 h intervals) or co-administered with daunorubicine and enalaprilat (i.p., 5 mg/kg in 12 h intervals). Control animals received vehicle. Left ventricular function was measured invasively under anesthesia. Cell-shortening was measured by videomicroscopy in isolated cardiomyocytes. Expression of PPARs mRNA in cardiac tissue was measured by Real-Time PCR. Although the hemodynamic parameters of daunorubicin-treated rats remained altered upon ACEi co-administration, ACEi normalized daunorubicin-induced QT prolongation. On cellular level, ACEi normalized altered basal and isoproterenol-stimulated cardiac cell shortening in daunorubicine-treated group. Moreover, anthracycline administration significantly up-regulated heart PPARα mRNA and its expression remained increased after ACEi co-administration. On the other hand, the expression of cardiac PPARβ/δ was not altered in anthracycline-treated animals, whereas co-administration of ACEi increased its expression. Conclusively, effect of ACEi can be already detected in sub-acute phase of anthracycline-induced cardiotoxicity. Altered expression of heart PPARs may suggest these nuclear receptors as a novel target in anthracycline cardiomyopathy.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia.
authors.forename: Hana
authors.initials: H
authors.lastname: Cernecka
authors.forename: Katarina
authors.initials: K
authors.lastname: Ochodnicka-Mackovicova
authors.forename: Dana
authors.initials: D
authors.lastname: Kucerova
authors.forename: Jana
authors.initials: J
authors.lastname: Kmecova
authors.forename: Viera
authors.initials: V
authors.lastname: Nemcekova
authors.forename: Gabriel
authors.initials: G
authors.lastname: Doka
authors.forename: Jan
authors.initials: J
authors.lastname: Kyselovic
authors.forename: Peter
authors.initials: P
authors.lastname: Krenek
authors.forename: Peter
authors.initials: P
authors.lastname: Ochodnicky
authors.forename: Jan
authors.initials: J
authors.lastname: Klimas
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology*; D003630:Daunorubicin / Q000494:pharmacology*; D004195:Disease Models, Animal; D015773:Enalaprilat / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D047494:PPAR delta / Q000235:genetics*; D048068:PPAR-beta / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D047494:PPAR delta; D048068:PPAR-beta; D015773:Enalaprilat; D003630:Daunorubicin
keywords: ACEi (Angiotensin conversing enzyme inhibitor); Anthracycline; Cardiomyopathy; PPAR (Peroxisome proliferator-activated receptors)