Endothelial NADPH oxidase 4 protects against angiotensin II‐induced cardiac fibrosis and inflammation

Abstract

Aims Endothelial activation and inflammatory cell infiltration have important roles in the development of cardiac fibrosis induced by renin-angiotensin system activation. NADPH oxidases (Nox proteins) are expressed in endothelial cells (ECs) and alter their function. Previous studies indicated that Nox2 in ECs contributes to angiotensin II (AngII)-induced cardiac fibrosis. However, the effects of EC Nox4 on cardiac fibrosis are unknown. Methods and results Transgenic (TG) mice overexpressing endothelial-restricted Nox4 were studied alongside wild-type (WT) littermates as controls. At baseline, Nox4 TG mice had significantly enlarged hearts compared with WT, with elongated cardiomyocytes (increased by 18.5%, P < 0.01) and eccentric hypertrophy but well-preserved cardiac function by echocardiography and in vivo pressure-volume analysis. Animals were subjected to a chronic AngII infusion (AngII, 1.1 mg/kg/day) for 14 days. Whereas WT/AngII developed a 2.1-fold increase in interstitial cardiac fibrosis as compared with WT/saline controls (P < 0.01), TG/AngII mice developed significant less fibrosis (1.4-fold increase, P > 0.05), but there were no differences in cardiac hypertrophy or contractile function between the two groups. TG hearts displayed significantly decreased inflammatory cell infiltration with reduced levels of vascular cell adhesion molecule 1 in both the vasculature and myocardium compared with WT after AngII treatment. TG microvascular ECs stimulated with AngII in vitro supported significantly less leukocyte adhesion than WT ECs. Conclusions A chronic increase in endothelial Nox4 stimulates physiological cardiac hypertrophy and protects against AngII-induced cardiac fibrosis by inhibiting EC activation and the recruitment of inflammatory cells. Highlights • Mice with endothelium-specific overexpression of Nox4 (EndoNox4 TG) exhibit eccentric hypertrophy with well-preserved cardiac function at baseline. • EndoNox4 TG mice develop significantly less interstitial cardiac fibrosis in response to chronic pressure AngII stimulation, independent of cardiac hypertrophy. • Overexpression of Nox4 in endothelial cells reduces AngII-induced endothelial activation. • An increase in endothelial Nox4 inhibits AngII-induced recruitment of inflammatory cells in the heart.

Comparative Efficacy of Antihypertensive Agents in Flow-Mediated Vasodilation of Patients with Hypertension: Network Meta-Analysis of Randomized Controlled Trial

“…Mechanistic insights into the effects of antihypertensive medications on FMD have not been fully elucidated, however plausible explanations have been proposed. Oxidative stress [ 65 ] and inflammation [ 66 ] are the main causes of hypertension-related endothelial dysfunction, as both significant reduce the bioavailability of nitric oxide [ 67 ].Beyond this, elevated blood pressure may damage endothelial cells and, cause their irreversible damage [ 68 ]. ARB can promote the release of nitric oxide and accelerate the effect of acetylcholine on endothelium-dependent vasodilation [ 69 ].…”

The Interplay of Mitochondrial Oxidative Stress and Endoplasmic Reticulum Stress in Cardiovascular Fibrosis in Obese Rats

“…These effects were accompanied by an attenuation of ER stress at cardiac and vascular levels. In addition, ROS reduction and ER stress inhibition by MitoQ or 4-PBA, respectively, reduced the profibrotic actions of Ang II, whose levels are elevated in obese animals and involved in cardiovascular fibrosis associated with obesity in cardiac and vascular cells [ 35 , 36 ]. This suggests that interactions between ER stress and mitochondrial oxidative stress regulate downstream events and are responsible for fibrosis in the context of obesity.…”

Role of oxidative stress in calcific aortic valve disease and its therapeutic implications

“… 91 Endothelial NOX4 protects against chronic pressure-overload induced cardiac remodelling, 84 , 86 and AngII-stimulated myocardial fibrosis. 92 In the vasculature, NOX4 protects against endothelial dysfunction, leucocyte adhesion, inflammation, and atherosclerosis. 82 , 87 However, up-regulated vascular smooth muscle cell (VSMC) NOX4 correlates with VSMC dysfunction and plaque instability, whilst VSMC NOX4 deletion attenuates western-diet–induced atherosclerosis.…”