title: Downregulation of myogenic microRNAs in sub-chronic but not in sub-acute model of daunorubicin-induced cardiomyopathy.
abstract: Cardiac muscle-related microRNAs play important roles in cardiac development and disease by translational silencing of mRNAs, the dominant mechanism of microRNA action. To test whether they could be involved in daunorubicin-associated cardiomyopathy (DACM), we determined expression patterns of myomiRs in two distinct models of DACM. We used 10-12 weeks old male Wistar rats. In the sub-acute model, rats were administered with six doses of daunorubicin (DAU-A, 3 mg/kg, i.p., every 48 h). Rats were sacrificed two days after the last dose. In the sub-chronic model, anaesthetized rats were administered a single dose of daunorubicin (15 mg/kg, i.v., DAU-C). Age-matched controls (CON) received vehicle. Rats were sacrificed eight weeks later. Left ventricular (LV) functions (LV pressure, rate of pressure development, +dP/dt and decline, -dP/dt) were measured using left ventricular catheterization. Expressions of myomiRs (miR-208a, miR-499, miR-1 and miR-133a), markers of cardiac failure (atrial and brain natriuretic peptides genes; Nppa and Nppb) and myosin heavy chain genes (Myh6, Myh7, Myh7b) in cardiac tissue were determined by RT-PCR. Protein expression of gp91phox NADPH oxidase subunit was detected by immunoblotting. Both DAU groups exhibited a similar depression of LV function, and LV weight reduction, accompanied by an upregulation of natriuretic peptides, and a decrease of Myh6 to total Myh ratio (-18% in DAU-A and - 25% in DAU-C, as compared to controls; both P < 0.05). DAU-C, but not DAU-A rats had a 35% mortality rate and exhibited a significantly increased gp91phox expression (DAU-C: 197 ± 33 versus CON-C: 100 ± 11; P < 0.05). Interestingly, myomiRs levels were only reduced in DAU-C compared to CON-C (miR-208: -45%, miR-499: -30%, miR-1: -29%, miR- and miR133a: -25%; all P < 0.05) but were unaltered in DAU-A. The lack of myomiRs expression, particularly in sub-chronic model, suggests the loss of control of myomiRs network on late progression of DACM. We suppose that the poor inhibition of mRNA targets might contribute to chronic DACM.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Doka
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia.
authors.forename: Eva
authors.initials: E
authors.lastname: Malikova
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia.
authors.forename: Kristina
authors.initials: K
authors.lastname: Galkova
authors.affiliation: Human Anatomy Section, Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo and Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy.
authors.forename: Giampiero
authors.initials: G
authors.lastname: La Rocca
authors.affiliation: Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic. kruzliakpeter@gmail.com.
authors.forename: Peter
authors.initials: P
authors.lastname: Kruzliak
authors.affiliation: Department of Thoracic Surgery, Faculty of Medicine and Dentistry, Medical University of Silesia, Katowice, Poland.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Adamek
authors.affiliation: Central University Hospital of Asturias (HUCA), University of Oviedo, Oviedo, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Rodrigo
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia.
authors.forename: Peter
authors.initials: P
authors.lastname: Krenek
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia. klimas@fpharm.uniba.sk.
authors.forename: Jan
authors.initials: J
authors.lastname: Klimas
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003630:Daunorubicin / Q000009:adverse effects* / Q000494:pharmacology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects*; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis*; D009124:Muscle Proteins / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D035683:MicroRNAs; D009124:Muscle Proteins; D003630:Daunorubicin
keywords: Anthracycline; Cardiomyopathy; Gene expression; MicroRNA; Myosin heavy chain isoforms; NADPH oxidase