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

TY - JOUR

T1 - Endothelial NADPH oxidase-2 promotes interstitial cardiac fibrosis and diastolic dysfunction through proinflammatory effects and endothelial-mesenchymal transition

AU - Murdoch, Colin E.

AU - Chaubey, Sanjay

AU - Zeng, Lingfang

AU - Yu, Bin

AU - Ivetic, Aleksander

AU - Walker, Simon J.

AU - Vanhoutte, Davy

AU - Heymans, Stephane

AU - Grieve, David J.

AU - Cave, Alison C.

AU - Brewer, Alison C.

AU - Zhang, Min

AU - Shah, Ajay M.

PY - 2014/6/24

Y1 - 2014/6/24

N2 - 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.

AB - 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.

KW - inflammation mediators

KW - cardiomegaly

KW - cultured cells

KW - vascular endothelium

KW - fibrosis

KW - diastolic heart failure

KW - mesenchymal stromal cells

KW - left ventricular dysfunction

KW - membrane glycoproteins

KW - transgenic mice

KW - NADPH oxidase

KW - mice

U2 - 10.1016/j.jacc.2014.02.572

DO - 10.1016/j.jacc.2014.02.572

M3 - Article

C2 - 24681145

SN - 0735-1097

VL - 63

SP - 2734

EP - 2741

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

IS - 24

ER -