A critical role for Egr-1 during vascular remodelling in pulmonary arterial hypertension

Cardiovasc Res. 2014 Sep 1;103(4):573-84. doi: 10.1093/cvr/cvu169. Epub 2014 Jul 14.

Abstract

Aims: Pulmonary arterial hypertension (PAH) is characterized by the development of unique neointimal lesions in the small pulmonary arteries, leading to increased right ventricular (RV) afterload and failure. Novel therapeutic strategies are needed that target these neointimal lesions. Recently, the transcription factor Egr-1 (early growth response protein 1) was demonstrated to be up-regulated early in experimental neointimal PAH. Its effect on disease development, however, is unknown. We aimed to uncover a novel role for Egr-1 as a molecular inductor for disease development in PAH.

Methods and results: In experimental flow-associated PAH in rats, we investigated the effects of Egr-1 down-regulation on pulmonary vascular remodelling, including neointimal development, and disease progression. Intravenous administration of catalytic oligodeoxynucleotides (DNA enzymes, DNAzymes) resulted in down-regulation of pulmonary vascular Egr-1 expression. Compared with vehicle or scrambled DNAzymes, DNAzymes attenuated pulmonary vascular remodelling, including the development of occlusive neointimal lesions. Selective down-regulation of Egr-1 in vivo led to reduced expression of vascular PDGF-B, TGF-β, IL-6, and p53, resulting in a reduction of vascular proliferation and increased apoptosis. DNAzyme treatment further attenuated pulmonary vascular resistance, RV systolic pressure, and RV hypertrophy. In contrast, in non-neointimal PH rodents, DNAzyme treatment had no effect on pulmonary vascular and RV remodelling. Finally, pharmacological inhibition of Egr-1 with pioglitazone, a peroxisome proliferator activated receptor-γ ligand, attenuated vascular remodelling including the development of neointimal lesions.

Conclusions: These results indicate that Egr-1 governs pulmonary vascular remodelling and the development of characteristic vascular neointimal lesions in flow-associated PAH. Egr-1 is therefore a potential target for future PAH treatment.

Keywords: Congenital heart disease; Endothelial cell; Proliferation; Pulmonary vascular remodeling; Right ventricular failure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Down-Regulation
  • Early Growth Response Protein 1 / genetics
  • Early Growth Response Protein 1 / metabolism*
  • Hemodynamics / drug effects
  • Hypertension, Pulmonary / drug therapy
  • Hypertension, Pulmonary / pathology
  • Interleukin-6 / metabolism
  • Male
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / metabolism*
  • Oligodeoxyribonucleotides / pharmacology
  • Pulmonary Artery / drug effects
  • Pulmonary Artery / metabolism*
  • Pulmonary Artery / pathology
  • Rats, Wistar
  • Transforming Growth Factor beta / metabolism
  • Vascular Remodeling*

Substances

  • Early Growth Response Protein 1
  • Egr1 protein, rat
  • Interleukin-6
  • Oligodeoxyribonucleotides
  • Transforming Growth Factor beta