title: SERCA2a gene therapy restores microRNA-1 expression in heart failure via an Akt/FoxO3A-dependent pathway.
abstract: OBJECTIVE
  Impaired myocardial sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) activity is a hallmark of failing hearts, and SERCA2a gene therapy improves cardiac function in animals and patients with heart failure (HF). Deregulation of microRNAs has been demonstrated in HF pathophysiology. We studied the effects of therapeutic AAV9.SERCA2a gene therapy on cardiac miRNome expression and focused on regulation, expression, and function of miR-1 in reverse remodelled failing hearts.
  
  
  RESULTS
  We studied a chronic post-myocardial infarction HF model treated with AAV9.SERCA2a gene therapy. Heart failure resulted in a strong deregulation of the cardiac miRNome. miR-1 expression was decreased in failing hearts, but normalized in reverse remodelled hearts after AAV9.SERCA2a gene delivery. Increased Akt activation in cultured cardiomyocytes led to phosphorylation of FoxO3A and subsequent exclusion from the nucleus, resulting in miR-1 gene silencing. In vitro SERCA2a expression also rescued miR-1 in failing cardiomyocytes, whereas SERCA2a inhibition reduced miR-1 levels. In vivo, Akt and FoxO3A were highly phosphorylated in failing hearts, but reversed to normal by AAV9.SERCA2a, leading to cardiac miR-1 restoration. Likewise, enhanced sodium-calcium exchanger 1 (NCX1) expression during HF was normalized by SERCA2a gene therapy. Validation experiments identified NCX1 as a novel functional miR-1 target.
  
  
  CONCLUSIONS
  SERCA2a gene therapy of failing hearts restores miR-1 expression by an Akt/FoxO3A-dependent pathway, which is associated with normalized NCX1 expression and improved cardiac function.
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Carl-Neuberg-Str 1, 30625 Hannover, Germany.
authors.forename: Regalla
authors.initials: R
authors.lastname: Kumarswamy
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Lyon
authors.forename: Ingo
authors.initials: I
authors.lastname: Volkmann
authors.forename: Adam M
authors.initials: AM
authors.lastname: Mills
authors.forename: Julia
authors.initials: J
authors.lastname: Bretthauer
authors.forename: Aanchal
authors.initials: A
authors.lastname: Pahuja
authors.forename: Cornelia
authors.initials: C
authors.lastname: Geers-Knörr
authors.forename: Theresia
authors.initials: T
authors.lastname: Kraft
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: Kenneth T
authors.initials: KT
authors.lastname: Macleod
authors.forename: Sian E
authors.initials: SE
authors.lastname: Harding
authors.forename: Thomas
authors.initials: T
authors.lastname: Thum
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003331:Coronary Vessels; D015536:Down-Regulation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015316:Genetic Therapy / Q000379:methods*; D006333:Heart Failure / Q000628:therapy*; D007783:Lactones / Q000494:pharmacology; D008026:Ligation; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics*; D012717:Sesquiterpenes / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D019831:Sodium-Calcium Exchanger / Q000378:metabolism
chemical_list: C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007783:Lactones; C542191:MIRN1 microRNA, rat; D035683:MicroRNAs; D012717:Sesquiterpenes; D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1; C046319:thapsigargicin; D051057:Proto-Oncogene Proteins c-akt; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases