Preclinical Development of a MicroRNA-Based Therapy for Elderly Patients With Myocardial Infarction.
Aging populations show higher incidences of myocardial infarction (MI) and heart failure (HF). Cardiac remodeling post-MI leads to progressive impaired cardiac function caused by a disarray of several processes including derailed autophagy. Microribonucleic acids (miRNAs) are known to be key players in cardiovascular disease but their involvement in cardiac autophagy and aging is not well understood.



This study sought to identify new miRNA candidates that regulate cardiac autophagy and aging.



We exploited a high-throughput, fluorescence-activated cell sorting-based green fluorescent protein-LC3 detection method to measure the autophagic flux in cardiomyocytes after transfection of a precursor miRNA library consisting of 380 miRNAs. This was followed by a series of molecular and in vivo studies.



Together with additional expression screenings, we identified miR-22 as an abundant and strong inhibitor of the cardiac autophagy process. Cardiac miR-22 expression levels increased during aging of mice as well as in aging neonatal cardiomyocytes in vitro by a P53-dependent mechanism. Inhibition of miR-22 in aging cardiomyocytes in vitro activated autophagy and inhibited cellular hypertrophy. Pharmacological inhibition of miR-22 post-MI in older mice activated cardiac autophagy, prevented post-infarction remodeling, and improved cardiac function compared with control subjects. Interestingly, similar effects were less pronounced in younger mice with significantly lower cardiac miR-22 expression levels. In addition, circulating levels of miR-22 in 154 patients with systolic HF were highly associated with early mortality.



We concluded that miR-22 is an important regulator of cardiac autophagy and a potential therapeutic target, especially in the older myocardium. Finally, circulating miR-22 provides prognostic information for HF patients, highlighting miR-22 as a promising therapeutic and biomarker candidate for cardiovascular disorders.
Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.
Shashi Kumar
SK
Gupta
Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.
Ariana
A
Foinquinos
Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.
Sabrina
S
Thum
Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.
Janet
J
Remke
Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.
Karina
K
Zimmer
Service de cardiologie, Pôle cardio-vasculaire et pulmonaire, Centre Hospitalier Régional et Universitaire de Lille, France-Université de Lille II, Lille, France; Inserm U1167, Institut Pasteur de Lille, Lille, France.
Christophe
C
Bauters
Service de cardiologie, Pôle cardio-vasculaire et pulmonaire, Centre Hospitalier Régional et Universitaire de Lille, France-Université de Lille II, Lille, France.
Pascal
P
de Groote
Institute of Cardiovascular Regeneration, Goethe-University, Frankfurt am Main, Germany.
Reinier A
RA
Boon
Department of Cardiology, Maastricht University, Maastricht, the Netherlands.
Leon J
LJ
de Windt
Institute of Experimental and Clinical Pharmacology and Toxicology, Albert-Ludwigs-Universität Freiburg, Freiburg im Breisgau, Germany.
Sebastian
S
Preissl
Institute of Experimental and Clinical Pharmacology and Toxicology, Albert-Ludwigs-Universität Freiburg, Freiburg im Breisgau, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
Lutz
L
Hein
Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.
Sandor
S
Batkai
Service de cardiologie, Pôle cardio-vasculaire et pulmonaire, Centre Hospitalier Régional et Universitaire de Lille, France-Université de Lille II, Lille, France.
Florence
F
Pinet
Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany; Excellence Cluster REBIRTH, Hannover Medical School, Hannover, Germany; National Heart and Lung Institute, Imperial College, London, United Kingdom. Electronic address: Thum.Thomas@mh-hannover.de.
Thomas
T
Thum
D000368:Aged; D000818:Animals; D001343:Autophagy / Q000235:genetics*; D015415:Biomarkers / Q000097:blood; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006333:Heart Failure / Q000097:blood / Q000235:genetics; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000097:blood / Q000502:physiology*; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D032383:Myocytes, Cardiac
D015415:Biomarkers; C548375:MIRN22 microRNA, human; D035683:MicroRNAs; C574876:Mirn22 microRNA, mouse
MiR-22; aging; autophagy; circulating miRNA; p62