Abstract
Objectives
To investigate the effect of endothelial dysfunction on development of cardiac hypertrophy and fibrosis.
Background
Endothelial dysfunction accompanies cardiac hypertrophy and fibrosis but its contribution to these conditions is unclear. Increased NADPH oxidase-2 (NOX2) activation causes endothelial dysfunction.
Methods
Transgenic mice with endothelial-specific NOX2 overexpression (TG) and wild-type littermates received chronic AngII infusion (1.1mg/kg/day, 2 weeks) to induce hypertrophy and fibrosis.
Results
TG had similar systolic hypertension and hypertrophy to wild-type but developed greater cardiac fibrosis and evidence of isolated left ventricular diastolic dysfunction (P<0.05). TG myocardium had more inflammatory cells and VCAM-1-positive vessels than wild-type after AngII (both P<0.05). TG microvascular endothelial cells (EC) treated with AngII recruited 2-fold more leukocytes than wild-type in an in vitro adhesion assay (P<0.05). However, inflammatory cell NOX2 per se was not essential for the pro-fibrotic effects of AngII. TG mice showed a higher level of endothelial-mesenchymal transition (EMT) than wild-type after AngII infusion. In cultured EC treated with AngII, NOX2 enhanced EMT as assessed by the relative expression of fibroblast versus endothelial-specific markers.
Conclusion
AngII-induced endothelial NOX2 activation has profound pro-fibrotic effects in the heart in vivo, leading to a diastolic dysfunction phenotype. Endothelial NOX2 enhances EMT and has pro-inflammatory effects. This may be an important mechanism underlying cardiac fibrosis and diastolic dysfunction during increased renin-angiotensin activation.
To investigate the effect of endothelial dysfunction on development of cardiac hypertrophy and fibrosis.
Background
Endothelial dysfunction accompanies cardiac hypertrophy and fibrosis but its contribution to these conditions is unclear. Increased NADPH oxidase-2 (NOX2) activation causes endothelial dysfunction.
Methods
Transgenic mice with endothelial-specific NOX2 overexpression (TG) and wild-type littermates received chronic AngII infusion (1.1mg/kg/day, 2 weeks) to induce hypertrophy and fibrosis.
Results
TG had similar systolic hypertension and hypertrophy to wild-type but developed greater cardiac fibrosis and evidence of isolated left ventricular diastolic dysfunction (P<0.05). TG myocardium had more inflammatory cells and VCAM-1-positive vessels than wild-type after AngII (both P<0.05). TG microvascular endothelial cells (EC) treated with AngII recruited 2-fold more leukocytes than wild-type in an in vitro adhesion assay (P<0.05). However, inflammatory cell NOX2 per se was not essential for the pro-fibrotic effects of AngII. TG mice showed a higher level of endothelial-mesenchymal transition (EMT) than wild-type after AngII infusion. In cultured EC treated with AngII, NOX2 enhanced EMT as assessed by the relative expression of fibroblast versus endothelial-specific markers.
Conclusion
AngII-induced endothelial NOX2 activation has profound pro-fibrotic effects in the heart in vivo, leading to a diastolic dysfunction phenotype. Endothelial NOX2 enhances EMT and has pro-inflammatory effects. This may be an important mechanism underlying cardiac fibrosis and diastolic dysfunction during increased renin-angiotensin activation.
| Original language | English |
|---|---|
| Pages (from-to) | 2734-2741 |
| Number of pages | 8 |
| Journal | Journal of the American College of Cardiology |
| Volume | 63 |
| Issue number | 24 |
| Early online date | 26 Mar 2014 |
| DOIs | |
| Publication status | Published - 24 Jun 2014 |