title: Targeted deletion of microRNA-22 promotes stress-induced cardiac dilation and contractile dysfunction.
abstract: BACKGROUND
  Delineating the role of microRNAs (miRNAs) in the posttranscriptional gene regulation offers new insights into how the heart adapts to pathological stress. We developed a knockout of miR-22 in mice and investigated its function in the heart.
  
  
  RESULTS
  Here, we show that miR-22-deficient mice are impaired in inotropic and lusitropic response to acute stress by dobutamine. Furthermore, the absence of miR-22 sensitized mice to cardiac decompensation and left ventricular dilation after long-term stimulation by pressure overload. Calcium transient analysis revealed reduced sarcoplasmic reticulum Ca(2+) load in association with repressed sarcoplasmic reticulum Ca(2+) ATPase activity in mutant myocytes. Genetic ablation of miR-22 also led to a decrease in cardiac expression levels for Serca2a and muscle-restricted genes encoding proteins in the vicinity of the cardiac Z disk/titin cytoskeleton. These phenotypes were attributed in part to inappropriate repression of serum response factor activity in stressed hearts. Global analysis revealed increased expression of the transcriptional/translational repressor purine-rich element binding protein B, a highly conserved miR-22 target implicated in the negative control of muscle expression.
  
  
  CONCLUSIONS
  These data indicate that miR-22 functions as an integrator of Ca(2+) homeostasis and myofibrillar protein content during stress in the heart and shed light on the mechanisms that enhance propensity toward heart failure.
authors.affiliation: Baylor College of Medicine, Department of Molecular and Human Genetics, One Baylor Plaza, Houston, TX, 77030, USA.
authors.forename: Priyatansh
authors.initials: P
authors.lastname: Gurha
authors.forename: Cei
authors.initials: C
authors.lastname: Abreu-Goodger
authors.forename: Tiannan
authors.initials: T
authors.lastname: Wang
authors.forename: Maricela O
authors.initials: MO
authors.lastname: Ramirez
authors.forename: Ana L
authors.initials: AL
authors.lastname: Drumond
authors.forename: Stijn
authors.initials: S
authors.lastname: van Dongen
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Chen
authors.forename: Nenad
authors.initials: N
authors.lastname: Bartonicek
authors.forename: Anton J
authors.initials: AJ
authors.lastname: Enright
authors.forename: Brendan
authors.initials: B
authors.lastname: Lee
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kelm
authors.forename: Anilkumar K
authors.initials: AK
authors.lastname: Reddy
authors.forename: George E
authors.initials: GE
authors.lastname: Taffet
authors.forename: Allan
authors.initials: A
authors.lastname: Bradley
authors.forename: Xander H
authors.initials: XH
authors.lastname: Wehrens
authors.forename: Mark L
authors.initials: ML
authors.lastname: Entman
authors.forename: Antony
authors.initials: A
authors.lastname: Rodriguez
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D026362:Serum Response Factor / Q000378:metabolism; D013312:Stress, Physiological / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D035683:MicroRNAs; C574876:Mirn22 microRNA, mouse; C108770:Purb protein, mouse; D026362:Serum Response Factor; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium