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Endothelial NADPH oxidase-2 promotes interstitial cardiac fibrosis and diastolic dysfunction through pro-inflammatory effects and endothelial-mesenchymal transition

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Colin Murdoch, Sanjay Chaubey, Lingfang Zeng, Bin Yu, Aleksander Ivetic, Simon J Walker, Davy Vanhoutte, Stephane Heymans, David J Grieve, Alison C Cave, Alison C Brewer, Min Zhang, Ajay M Shah, Alex Ivetic

Original languageEnglish
Pages (from-to)2734-2741
Number of pages8
JournalJournal of the American College of Cardiology
Issue number24
Publication statusPublished - 24 Jun 2014

King's Authors


To investigate the effect of endothelial dysfunction on development of cardiac hypertrophy and fibrosis.

Endothelial dysfunction accompanies cardiac hypertrophy and fibrosis but its contribution to these conditions is unclear. Increased NADPH oxidase-2 (NOX2) activation causes endothelial dysfunction.

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.

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.

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.

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