title: Ramipril restores PPARβ/δ and PPARγ expressions and reduces cardiac NADPH oxidase but fails to restore cardiac function and accompanied myosin heavy chain ratio shift in severe anthracycline-induced cardiomyopathy in rat.
abstract: We hypothesized that peroxisome proliferator-activated receptors (PPARs) might be involved in a complex protective action of ACE inhibitors (ACEi) in anthracyclines-induced cardiomyopathy. For purpose of study, we compared effects of ramipril on cardiac dysfunction, cardiac failure markers and PPAR isoforms in moderate and severe chronic daunorubicin-induced cardiomyopathy. Male Wistar rats were administered with a single intravenous injection of daunorubicin: 5mg/kg (moderate cardiomyopathy), or 15mg/kg (severe cardiomyopathy) or co-administered with daunorubicin and ramipril (1mg/kg/d, orally) or vehicle for 8 weeks. Left ventricular function was measured invasively under anesthesia. Cardiac mRNA levels of heart failure markers (ANP, Myh6, Myh7, Myh7b) and PPARs (alpha, beta/delta and gama) were measured by qRT-PCR. Protein expression of NADPH subunit (gp91phox) was measured by Western blot. Moderate cardiomyopathy exhibited only minor cardiac dysfunction what was corrected by ramipril. In severe cardiomyopathy, hemodynamic dysfunction remained unaltered upon ramipril although it decreased the significantly up-regulated cardiac ANP mRNA expression. Simultaneously, while high-dose daunorubicin significantly decreased PPARbeta/delta and PPARgama mRNA, ramipril normalized these abnormalities. Similarly, ramipril reduced altered levels of oxidative stress-related gp91phox. On the other hand, ramipril was unable to correct both the significantly decreased relative abundance of Myh6 and increased Myh7 mRNA levels, respectively. In conclusion, ramipril had a protective effect on cardiac function exclusively in moderate chronic daunorubicin-induced cardiomyopathy. Although it normalized abnormal PPARs expression and exerted also additional protective effects also in severe cardiomyopathy, it was insufficient to influence impaired cardiac function probably because of a shift in myosin heavy chain isoform content.
authors: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia; Bayer Pharma AG, Wuppertal, Germany.
authors: Hana
authors: H
authors: Cernecka
authors: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia.
authors: Gabriel
authors: G
authors: Doka
authors: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia.
authors: Jasna
authors: J
authors: Srankova
authors: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia.
authors: Lenka
authors: L
authors: Pivackova
authors: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia.
authors: Eva
authors: E
authors: Malikova
authors: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia.
authors: Kristina
authors: K
authors: Galkova
authors: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia.
authors: Jan
authors: J
authors: Kyselovic
authors: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia.
authors: Peter
authors: P
authors: Krenek
authors: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia. Electronic address: klimas1@uniba.sk.
authors: Jan
authors: J
authors: Klimas
mesh_terms: D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D018943:Anthracyclines / Q000494:pharmacology; D009202:Cardiomyopathies / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D018995:Myosin Heavy Chains / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D047494:PPAR delta / Q000235:genetics; D047495:PPAR gamma / Q000235:genetics; D048068:PPAR-beta / Q000235:genetics; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017257:Ramipril / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018943:Anthracyclines; D047494:PPAR delta; D047495:PPAR gamma; D048068:PPAR-beta; D047492:Peroxisome Proliferator-Activated Receptors; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D009569:Nitric Oxide; D019255:NADPH Oxidases; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; D018995:Myosin Heavy Chains; D017257:Ramipril
keywords: Angiotensin-converting enzyme inhibitor; Anthracycline; Chronic cardiomyopathy; Myosin heavy chain isoforms; Peroxisome proliferator-activated receptors