Potential role of microRNA-10b down-regulation in cardiomyocyte apoptosis in aortic stenosis patients.
MicroRNAs have been associated with cardiomyocyte apoptosis, a process involved in myocardial remodelling in aortic valve (Av) stenosis (AS). Our aim was to analyse whether the dysregulation of myocardial microRNAs was related to cardiomyocyte apoptosis in AS patients. Endomyocardial biopsies were obtained from 28 patients with severe AS (based on pressure gradients and Av area) referred for Av replacement and from necropsies of 10 cardiovascular disease-free control subjects. AS patients showed an increased (P<0.001) cardiomyocyte apoptotic index (CMAI) compared with controls. Two clusters of patients were identified according to the CMAI: group 1 (CMAI ≤ 0.08%; n=16) and group 2 (CMAI > 0.08%; n=12). Group 2 patients presented lower cardiomyocyte density (P<0.001) and ejection fraction (P<0.05), and higher troponin T levels (P<0.05), prevalence of heart failure (HF; P<0.05) and NT-proBNP levels (P<0.05) than those from group 1. miRNA expression profile analysed in 5 patients randomly selected from each group showed 64 microRNAs down-regulated and 6 up-regulated (P<0.05) in group 2 compared with group 1. Those microRNAs with the highest fold-change were validated in the full two groups corroborating that miR-10b, miR-125b-2* and miR-338-3p were down-regulated (P<0.05) in group 2 compared with group 1 and control subjects. These three microRNAs were inversely correlated (P<0.05) with the CMAI. Inhibition of miR-10b induced an increase (P<0.05) of apoptosis and increased expression (P<0.05) of apoptosis protease-activating factor-1 (Apaf-1) in HL-1 cardiomyocytes. In conclusion, myocardial down-regulation of miR-10b may be involved in increased cardiomyocyte apoptosis in AS patients, probably through Apaf-1 up-regulation, contributing to cardiomyocyte damage and to the development of HF.
Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona 31008, Spain.|IdiSNA, Navarra Institute for Health Research, Pamplona 31008, Spain.
Idoia
I
Gallego
Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona 31008, Spain.|IdiSNA, Navarra Institute for Health Research, Pamplona 31008, Spain.
Javier
J
Beaumont
Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona 31008, Spain.|IdiSNA, Navarra Institute for Health Research, Pamplona 31008, Spain.
Begoña
B
López
Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona 31008, Spain.|IdiSNA, Navarra Institute for Health Research, Pamplona 31008, Spain.
Susana
S
Ravassa
Division of Cardiology, Virgen de la Victoria University Hospital, Málaga 29010, Spain.
Juan José
JJ
Gómez-Doblas
Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona 31008, Spain.|IdiSNA, Navarra Institute for Health Research, Pamplona 31008, Spain.
María Ujué
MU
Moreno
Division of Cardiology, Virgen de la Victoria University Hospital, Málaga 29010, Spain.
Félix
F
Valencia
Division of Cardiology, Virgen de la Victoria University Hospital, Málaga 29010, Spain.
Eduardo
E
de Teresa
Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona 31008, Spain amiqueo@unav.es jadimar@unav.es.|IdiSNA, Navarra Institute for Health Research, Pamplona 31008, Spain.|Department of Cardiology and Cardiac Surgery, University Clinic, University of Navarra, Pamplona 31008, Spain.
Javier
J
Díez
Program of Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona 31008, Spain amiqueo@unav.es jadimar@unav.es.|IdiSNA, Navarra Institute for Health Research, Pamplona 31008, Spain.
Arantxa
A
González
D000368:Aged; D001024:Aortic Valve Stenosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D017209:Apoptosis; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*; D020107:Troponin T / Q000235:genetics / Q000378:metabolism
C547183:MIRN10 microRNA, human; D035683:MicroRNAs; D020107:Troponin T
aortic valve stenosis; cardiomyocyte apoptosis; heart failure; miR-10b; microRNAs