title: Increased microRNA-1 and microRNA-133a levels in serum of patients with cardiovascular disease indicate myocardial damage.
abstract: BACKGROUND
  Recently, elevation of circulating muscle-specific microRNA (miRNA) levels has been reported in patients with acute myocardial infarction. However, it is still unclear from which part of the myocardium or under what conditions miRNAs are released into circulating blood. The purpose of this study was to identify the source of elevated levels of circulating miRNAs and their function in cardiovascular diseases.
  
  
  RESULTS
  Serum levels of miRNA (miR)-1 and miR-133a were increased significantly in patients not only with acute myocardial infarction but also with unstable angina pectoris and Takotsubo cardiomyopathy without elevation of serum creatine phosphokinase or cardiac troponin. MicroRNA microarray analysis of the heart from a mouse model of myocardial infarction indicated that the levels of miR-1, miR-133a, miR-208a, and miR-499 were significantly reduced in the infarcted myocardium. In situ hybridization of miR-133a also showed that miR-133a levels were very low in the infarcted and peri-infarcted myocardium. It has been shown that circulating miRNAs are localized inside exosomes, which are released after Ca(2+) stimulation. We stimulated H9c2 cardiomyoblasts with A23187 and measured miR-133a levels in the exosome fraction of the culture medium. A23187 induced a dose-dependent release of miR-133a, and significant elevation was observed only at concentrations where dead cells were detected. We also found that miR-133a-containing exosomes reduced the luciferase activity of 293FT cells transfected with an miR-133a sensor vector.
  
  
  CONCLUSIONS
  These results suggest that elevated levels of circulating miR-133a in patients with cardiovascular diseases originate mainly from the injured myocardium. Circulating miR-133a can be used as a marker for cardiomyocyte death, and it may have functions in cardiovascular diseases.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Kuwabara
authors.forename: Koh
authors.initials: K
authors.lastname: Ono
authors.forename: Takahiro
authors.initials: T
authors.lastname: Horie
authors.forename: Hitoo
authors.initials: H
authors.lastname: Nishi
authors.forename: Kazuya
authors.initials: K
authors.lastname: Nagao
authors.forename: Minako
authors.initials: M
authors.lastname: Kinoshita
authors.forename: Shin
authors.initials: S
authors.lastname: Watanabe
authors.forename: Osamu
authors.initials: O
authors.lastname: Baba
authors.forename: Yoji
authors.initials: Y
authors.lastname: Kojima
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shizuta
authors.forename: Masao
authors.initials: M
authors.lastname: Imai
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Tamura
authors.forename: Toru
authors.initials: T
authors.lastname: Kita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kimura
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D002118:Calcium; D002318:Cardiovascular Diseases / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D016923:Cell Death; D055354:Exosomes; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000097:blood* / Q000502:physiology; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000473:pathology
chemical_list: D015415:Biomarkers; C544547:MIRN1 microRNA, human; C548234:MIRN133 microRNA, human; D035683:MicroRNAs; D002118:Calcium