title: Angiotensin II type 1 receptor signalling regulates microRNA differentially in cardiac fibroblasts and myocytes.
abstract: OBJECTIVE
  The angiotensin II type 1 receptor (AT(1)R) is a key regulator of blood pressure and cardiac contractility and is profoundly involved in development of cardiac disease. Since several microRNAs (miRNAs) have been implicated in cardiac disease, we determined whether miRNAs might be regulated by AT(1)R signals in a Gαq/11-dependent or -independent manner.
  
  
  METHODS
  We performed a global miRNA array analysis of angiotensin II (Ang II)-mediated miRNA regulation in HEK293N cells overexpressing the AT(1)R and focused on separating the role of Gαq/11-dependent and -independent pathways. MiRNA regulation was verified with quantitative PCR in both HEK293N cells and primary cardiac myocytes and fibroblasts.
  
  
  RESULTS
  Our studies revealed five miRNAs (miR-29b, -129-3p, -132, -132* and -212) that were up-regulated by Ang II in HEK293N cells. In contrast, the biased Ang II analogue, [Sar1, Ile4, Ile8] Ang II (SII Ang II), which selectively activates Gαq/11-independent signalling, failed to regulate miRNAs in HEK293N cells. Furthermore, Ang II-induced miRNA regulation was blocked following Gαq/11 and Mek1 inhibition. The observed Ang II regulation of miRNA was confirmed in primary cultures of adult cardiac fibroblasts. Interestingly, Ang II did not regulate miRNA expression in cardiac myocytes, but SII Ang II significantly down-regulated miR-129-3p.
  
  
  CONCLUSIONS
  Five miRNAs were regulated by Ang II through mechanisms depending on Gαq/11 and Erk1/2 activation. These miRNAs may be involved in Ang II-mediated cardiac biology and disease, as several of these miRNAs have previously been associated with cardiovascular disease and were found to be regulated in cardiac cells.
authors: Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark and Department of Clinical Biochemistry & Pharmacology, Odense University Hospital, Odense, Denmark.
authors: Pia Lindgren
authors: PL
authors: Jeppesen
authors: Gitte Lund
authors: GL
authors: Christensen
authors: Mikael
authors: M
authors: Schneider
authors: Anne Yaël
authors: AY
authors: Nossent
authors: Hasse Brønnum
authors: HB
authors: Jensen
authors: Ditte Caroline
authors: DC
authors: Andersen
authors: Tilde
authors: T
authors: Eskildsen
authors: Steen
authors: S
authors: Gammeltoft
authors: Jakob Lerche
authors: JL
authors: Hansen
authors: Søren Paludan
authors: SP
authors: Sheikh
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000873:Anthracenes / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000502:physiology*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C544065:AGTR1 protein, human; D000873:Anthracenes; D002070:Butadienes; D007093:Imidazoles; D035683:MicroRNAs; D009570:Nitriles; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; C113580:U 0126; D000804:Angiotensin II; C432165:pyrazolanthrone; D048049:Extracellular Signal-Regulated MAP Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; C093642:SB 203580