ET-1 from endothelial cells is required for complete angiotensin II-induced cardiac fibrosis and hypertrophy

Life Sci. 2012 Oct 15;91(13-14):651-7. doi: 10.1016/j.lfs.2012.02.006. Epub 2012 Feb 16.


Aims: Hypertensive patients develop cardiac hypertrophy and fibrosis with increased stiffness, contractile deficit and altered perfusion. Angiotensin II (AngII) is an important factor in the promotion of this pathology. The effects of AngII are partly mediated by endothelin-1 (ET-1) and transforming growth factor-β. The exact feature of these pathways and the intercellular communications involved remain unclear. In this study, we explored the role of endothelial cell-derived ET-1 in the development of AngII-induced cardiac fibrosis and hypertrophy.

Main methods: We used mice with vascular endothelial cell specific ET-1 deficiency (VEETKO) and their wild type littermates (WT). Mice were infused for one week with AngII (3.2mg/kg/day, n=12) or vehicle (0.15 mol/L NaCl and 1 mmol/L acetic acid, n=5), using subcutaneous mini-pumps. Hearts were stained with hematoxylin-eosin and masson's trichrome for histology. Cardiac gene expression and protein abundance were measured by Northern Blot, real time PCR and Western Blot.

Key findings: AngII-induced cardiac hypertrophy, interstitial and perivascular fibrosis were less pronounced in VEETKO mice compared to WT. Blood pressure increased similarly in both genotypes. Expression of connective tissue growth factor, tumor growth factor-β, collagen I and III in response to AngII required endothelial ET-1. Endothelial ET-1 was also necessary to the elevation in protein kinase C δ abundance and ERK1/2 activation. AngII-induced elevation in PKCε abundance was however ET-1 independent.

Significance: This study underscores the significance of ET-1 from the vasculature in the process of AngII-induced cardiac hypertrophy and fibrosis, independently from blood pressure. Endothelial ET-1 represents therefore a possible pharmacological target.

MeSH terms

  • Angiotensin II / administration & dosage
  • Animals
  • Blood Pressure
  • Blotting, Northern
  • Blotting, Western
  • Cardiomegaly / pathology*
  • Disease Models, Animal
  • Endothelial Cells / metabolism*
  • Endothelin-1 / genetics
  • Endothelin-1 / metabolism*
  • Fibrosis
  • Gene Expression Regulation
  • Male
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Myocardium / pathology*
  • Polymerase Chain Reaction
  • Protein Kinase C-delta / metabolism
  • Protein Kinase C-epsilon / metabolism


  • Endothelin-1
  • Angiotensin II
  • Protein Kinase C-delta
  • Protein Kinase C-epsilon
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3