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

Murdoch, Colin E., Chaubey, Sanjay, Zeng, Lingfang, Yu, Bin, Ivetic, Aleksander, Walker, Simon J., Vanhoutte, Davy, Heymans, Stephane, Grieve, David J., Cave, Alison C., Brewer, Alison C., Zhang, Min and Shah, Ajay M. (2014). Endothelial NADPH oxidase-2 promotes interstitial cardiac fibrosis and diastolic dysfunction through proinflammatory effects and endothelial-mesenchymal transition. Journal of the American College of Cardiology, 63 (24), pp. 2734-2741.

Abstract

OBJECTIVES: This study sought to investigate the effect of endothelial dysfunction on the development of cardiac hypertrophy and fibrosis. BACKGROUND: Endothelial dysfunction accompanies cardiac hypertrophy and fibrosis, but its contribution to these conditions is unclear. Increased nicotinamide adenine dinucleotide phosphate oxidase-2 (NOX2) activation causes endothelial dysfunction. METHODS: Transgenic mice with endothelial-specific NOX2 overexpression (TG mice) and wild-type littermates received long-term angiotensin II (AngII) infusion (1.1 mg/kg/day, 2 weeks) to induce hypertrophy and fibrosis. RESULTS: TG mice had systolic hypertension and hypertrophy similar to those seen in wild-type mice 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 did wild-type myocardium after AngII treatment (both p < 0.05). TG microvascular endothelial cells (ECs) treated with AngII recruited 2-fold more leukocytes than did wild-type ECs in an in vitro adhesion assay (p < 0.05). However, inflammatory cell NOX2 per se was not essential for the profibrotic effects of AngII. TG showed a higher level of endothelial-mesenchymal transition (EMT) than did wild-type mice after AngII infusion. In cultured ECs treated with AngII, NOX2 enhanced EMT as assessed by the relative expression of fibroblast versus endothelial-specific markers. CONCLUSIONS: AngII-induced endothelial NOX2 activation has profound profibrotic effects in the heart in vivo that lead to a diastolic dysfunction phenotype. Endothelial NOX2 enhances EMT and has proinflammatory effects. This may be an important mechanism underlying cardiac fibrosis and diastolic dysfunction during increased renin-angiotensin activation.

Publication DOI: https://doi.org/10.1016/j.jacc.2014.02.572
Divisions: Life & Health Sciences > Biosciences
Aston Medical School
Additional Information: © 2014, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/
Uncontrolled Keywords: inflammation mediators,cardiomegaly,cultured cells,vascular endothelium,fibrosis,diastolic heart failure,mesenchymal stromal cells,left ventricular dysfunction,membrane glycoproteins,transgenic mice,NADPH oxidase,mice
Published Date: 2014-06-24
Authors: Murdoch, Colin E. ( 0000-0002-0274-819X)
Chaubey, Sanjay
Zeng, Lingfang
Yu, Bin
Ivetic, Aleksander
Walker, Simon J.
Vanhoutte, Davy
Heymans, Stephane
Grieve, David J.
Cave, Alison C.
Brewer, Alison C.
Zhang, Min
Shah, Ajay M.

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