title: Transcriptome characterization of estrogen-treated human myocardium identifies myosin regulatory light chain interacting protein as a sex-specific element influencing contractile function.
abstract: OBJECTIVE
  This study investigated the effects of 17β-estradiol (E2) on gene regulation in human cardiac tissues. We hypothesized that a candidate E2 effect is cardiomyocyte (CM)- and sex-specific, conserved between humans and mice, and that E2 impairs contractile function in male CMs only.
  
  
  BACKGROUND
  Both men and women produce E2 locally from androgenic precursors. E2 regulates cardiovascular function, but specific mechanisms, protective or harmful, are not fully understood.
  
  
  METHODS
  We performed genome-wide expression profiling of E2-treated cardiac tissues from men and women, and studied gene expression and function in CMs from hearts of male and female E2-treated mice.
  
  
  RESULTS
  We found 36 E2-dependent genes regulated in a sex-specific manner. Of these, after E2 exposure, the myosin regulatory light chain interacting protein (MYLIP) gene was induced in tissues of men only. Focusing on Mylip and employing isolated mouse CMs, we confirmed our hypotheses that the E2 effect is CM- and sex-specific and conserved between humans and mice. The E2-treatment led to impaired contractile function in male CMs only, which was characterized by increased Mylip mRNA and protein levels, and decreased myosin regulatory light chain (Mrlc) protein. Our report is the first to our knowledge to show that cardiac Mrlc is an in vivo substrate for Mylip, leading to augmented Mrlc ubiquitination. Of relevance, we found that MYLIP expression levels rise with increasing age in hearts of men.
  
  
  CONCLUSIONS
  E2 directly influences cardiac gene regulation, and E2 actions may be different between the sexes. Since E2 levels rise in older and/or obese men, pharmacological targeting of MYLIP in men with elevated E2 levels could possibly decrease their risk for the development or progression of cardiovascular disease.
authors.affiliation: Institute of Gender in Medicine and Center for Cardiovascular Research, Charite University Hospital, Hessische Strasse 3-4, Berlin, Germany. georgios.kararigas@charite.de
authors.forename: Georgios
authors.initials: G
authors.lastname: Kararigas
authors.forename: Virginie
authors.initials: V
authors.lastname: Bito
authors.forename: Hanna
authors.initials: H
authors.lastname: Tinel
authors.forename: Eva
authors.initials: E
authors.lastname: Becher
authors.forename: Istvan
authors.initials: I
authors.lastname: Baczko
authors.forename: Christoph
authors.initials: C
authors.lastname: Knosalla
authors.forename: Barbara
authors.initials: B
authors.lastname: Albrecht-Küpper
authors.forename: Karin R
authors.initials: KR
authors.lastname: Sipido
authors.forename: Vera
authors.initials: V
authors.lastname: Regitz-Zagrosek
mesh_terms: D000328:Adult; D000375:Aging / Q000378:metabolism; D000818:Animals; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018994:Myosin Light Chains / Q000378:metabolism; D012727:Sex Characteristics; D059467:Transcriptome; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D018994:Myosin Light Chains; D004958:Estradiol; C403126:MYLIP protein, human; D044767:Ubiquitin-Protein Ligases