Cardiovascular pharmacology Enalaprilat increases PPARβ/δ expression, without influence on PPARα and PPARγ, and modulate cardiac function in sub-acute model of daunorubicin-induced cardiomyopathy Hana Cernecka a,1 , Katarina Ochodnicka-Mackovicova a,1 , Dana Kucerova a , Jana Kmecova a , Viera Nemcekova b , Gabriel Doka a , Jan Kyselovic a , Peter Krenek a , Peter Ochodnicky a , Jan Klimas a,n a Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia b Hospital of Ministry of Internal Affairs, Department of Functional Diagnostics, Bratislava, Slovakia article info Article history: Received 7 December 2012 Received in revised form 17 June 2013 Accepted 21 June 2013 Available online 5 July 2013 Keywords: Anthracycline Cardiomyopathy ACEi (Angiotensin conversing enzyme inhibitor) PPAR (Peroxisome proliferator-activated receptors) 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 anthracy- cline 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 normal- ized 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. & 2013 Elsevier B.V. All rights reserved. 1. Introduction Anthracyclines, such as daunorubicin, doxorubicin or epirubicin are highly effective and widely used anti-tumor agents although their clinical use is limited by dose-dependent cardiotoxicity, leading to congestive heart failure and death (Singal and Iliskovic, 1998). Supported by many studies, free radical-induced oxidative stress has been implied to play a principal role but, controversially, the clinical application of antioxidants in daunorubicin-induced cardiotoxicity provided ambiguous evidence (Simunek et al., 2009). Since angio- tensin II (Ang II) has been implicated in the progression of other cardiomyopathies (Oudit et al., 2007), angiotensin conversing enzyme inhibitors (ACEi) were employed to prevent the deteriora- tion of late-onset anthracycline cardiomyopathy (Boucek et al., 2003). Currently, the management of congestive heart failure in cancer survivors may involve also ACEi (Jensen et al., 1996). However, the cardioprotective potential of ACEi administration during anthracycline treatment remains controversial. In long- term survivors of pediatric cancer, enalapril may be beneficial in the intermediate follow-up of asymptomatic LV dysfunction and in the short-term follow-up of heart failure but does not prevent progressive LV wall damage (Lipshultz et al., 2002). Healthy adult heart is dependent of fatty acids. During devel- opment of congestive heart failure, it has been shown that myocardium switches to using glucose as a main ATP source instead of fatty acids (van Bilsen et al., 2004). Peroxisome proliferator-activated receptors (PPARs) orchestrate the cellular lipid metabolism and, consequently, they might play a major role in the development of the cardiac disease. PPARs constitute the Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/ejphar European Journal of Pharmacology 0014-2999/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejphar.2013.06.040 n Corresponding author. Tel.: +421 250117115. E-mail address: klimas@fpharm.uniba.sk (J. Klimas). 1 Both authors contributed to this work equally. European Journal of Pharmacology 714 (2013) 472–477