Adenoviral delivery of angiotensin-(1-7) or angiotensin-(1-9) inhibits cardiomyocyte hypertrophy via the mas or angiotensin type 2 receptor

PLoS One. 2012;7(9):e45564. doi: 10.1371/journal.pone.0045564. Epub 2012 Sep 20.


The counter-regulatory axis of the renin angiotensin system peptide angiotensin-(1-7) [Ang-(1-7)] has been identified as a potential therapeutic target in cardiac remodelling, acting via the mas receptor. Furthermore, we recently reported that an alternative peptide, Ang-(1-9) also counteracts cardiac remodelling via the angiotensin type 2 receptor (AT(2)R). Here, we have engineered adenoviral vectors expressing fusion proteins which release Ang-(1-7) [RAdAng-(1-7)] or Ang-(1-9) [RAdAng-(1-9)] and compared their effects on cardiomyocyte hypertrophy in rat H9c2 cardiomyocytes or primary adult rabbit cardiomyocytes, stimulated with angiotensin II, isoproterenol or arg-vasopressin. RAdAng-(1-7) and RAdAng-(1-9) efficiently transduced cardiomyocytes, expressed fusion proteins and secreted peptides, as demonstrated by western immunoblotting and conditioned media assays. Furthermore, secreted Ang-(1-7) and Ang-(1-9) inhibited cardiomyocyte hypertrophy (Control = 168.7±8.4 µm; AngII = 232.1±10.7 µm; AngII+RAdAng-(1-7) = 186±9.1 µm, RAdAng-(1-9) = 180.5±9 µm; P<0.05) and these effects were selectively reversed by inhibitors of their cognate receptors, the mas antagonist A779 for RAdAng-(1-7) and the AT(2)R antagonist PD123,319 for RAdAng-(1-9). Thus gene transfer of Ang-(1-7) and Ang-(1-9) produces receptor-specific effects equivalent to those observed with addition of exogenous peptides. These data highlight that Ang-(1-7) and Ang-(1-9) can be expressed via gene transfer and inhibit cardiomyocyte hypertrophy via their respective receptors. This supports applications for this approach for sustained peptide delivery to study molecular effects and potential gene therapeutic actions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics*
  • Angiotensin I / chemistry
  • Angiotensin I / genetics*
  • Angiotensin I / metabolism
  • Animals
  • Cardiomegaly / genetics*
  • Cardiomegaly / metabolism
  • Cardiomegaly / therapy
  • Cell Line
  • Genetic Therapy
  • Genetic Vectors
  • Humans
  • Myocytes, Cardiac / metabolism*
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics*
  • Peptide Fragments / metabolism
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins / metabolism*
  • Rabbits
  • Rats
  • Receptor, Angiotensin, Type 2 / metabolism*
  • Receptors, G-Protein-Coupled / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Transduction, Genetic


  • Peptide Fragments
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins
  • Receptor, Angiotensin, Type 2
  • Receptors, G-Protein-Coupled
  • Recombinant Fusion Proteins
  • angiotensin I (1-9)
  • Angiotensin I
  • angiotensin I (1-7)

Grants and funding

The authors thank University of Glasgow Postgraduate Scholarship Scheme and Consejo Nacional de Ciencia y Tecnologia (CONACYT) for funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.