title: MicroRNA-18 and microRNA-19 regulate CTGF and TSP-1 expression in age-related heart failure.
abstract: To understand the process of cardiac aging, it is of crucial importance to gain insight into the age-related changes in gene expression in the senescent failing heart. Age-related cardiac remodeling is known to be accompanied by changes in extracellular matrix (ECM) gene and protein levels. Small noncoding microRNAs regulate gene expression in cardiac development and disease and have been implicated in the aging process and in the regulation of ECM proteins. However, their role in age-related cardiac remodeling and heart failure is unknown. In this study, we investigated the aging-associated microRNA cluster 17-92, which targets the ECM proteins connective tissue growth factor (CTGF) and thrombospondin-1 (TSP-1). We employed aged mice with a failure-resistant (C57Bl6) and failure-prone (C57Bl6 × 129Sv) genetic background and extrapolated our findings to human age-associated heart failure. In aging-associated heart failure, we linked an aging-induced increase in the ECM proteins CTGF and TSP-1 to a decreased expression of their targeting microRNAs 18a, 19a, and 19b, all members of the miR-17-92 cluster. Failure-resistant mice showed an opposite expression pattern for both the ECM proteins and the microRNAs. We showed that these expression changes are specific for cardiomyocytes and are absent in cardiac fibroblasts. In cardiomyocytes, modulation of miR-18/19 changes the levels of ECM proteins CTGF and TSP-1 and collagens type 1 and 3. Together, our data support a role for cardiomyocyte-derived miR-18/19 during cardiac aging, in the fine-tuning of cardiac ECM protein levels. During aging, decreased miR-18/19 and increased CTGF and TSP-1 levels identify the failure-prone heart.
authors.affiliation: Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
authors.forename: Geert C
authors.initials: GC
authors.lastname: van Almen
authors.forename: Wouter
authors.initials: W
authors.lastname: Verhesen
authors.forename: Rick E W
authors.initials: RE
authors.lastname: van Leeuwen
authors.forename: Mathijs
authors.initials: M
authors.lastname: van de Vrie
authors.forename: Casper
authors.initials: C
authors.lastname: Eurlings
authors.forename: Mark W M
authors.initials: MW
authors.lastname: Schellings
authors.forename: Melissa
authors.initials: M
authors.lastname: Swinnen
authors.forename: Jack P M
authors.initials: JP
authors.lastname: Cleutjens
authors.forename: Marc A M J
authors.initials: MA
authors.lastname: van Zandvoort
authors.forename: Stephane
authors.initials: S
authors.lastname: Heymans
authors.forename: Blanche
authors.initials: B
authors.lastname: Schroen
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000235:genetics / Q000502:physiology; D000818:Animals; D001706:Biopsy; D003094:Collagen / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism*; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000502:physiology; D006333:Heart Failure / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D005810:Multigene Family; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C526317:CCN2 protein, human; C526318:CCN2 protein, mouse; C526316:CCN2 protein, rat; C552691:MIRN18 microRNA, mouse; C549214:MIRN19A microRNA, human; C561642:MIRN19 microRNA, mouse; D035683:MicroRNAs; D019700:Thrombospondin 1; D055513:Connective Tissue Growth Factor; D003094:Collagen