NOX2 Is Critical to Endocardial to Mesenchymal Transition and Heart Development.

Hoda Moazzen,Simran Aulakh,Qingping Feng,Xiangru Lu,Yan Wu,Anish Engineer

doi:10.1155/2020/1679045

Abstract

NADPH oxidases (NOX) are a major source of reactive oxygen species (ROS) production in the heart. ROS signaling regulates gene expression, cell proliferation, apoptosis, and migration. However, the role of NOX2 in embryonic heart development remains elusive. We hypothesized that deficiency of Nox2 disrupts endocardial to mesenchymal transition (EndMT) and results in congenital septal and valvular defects. Our data show that 34% of Nox2−/− neonatal mice had various congenital heart defects (CHDs) including atrial septal defects (ASD), ventricular septal defects (VSD), atrioventricular canal defects (AVCD), and malformation of atrioventricular and aortic valves. Notably, Nox2−/− embryonic hearts show abnormal development of the endocardial cushion as evidenced by decreased cell proliferation and an increased rate of apoptosis. Additionally, Nox2 deficiency disrupted EndMT of atrioventricular cushion explants ex vivo. Furthermore, treatment with N-acetylcysteine (NAC) to reduce ROS levels in the wild-type endocardial cushion explants decreased the number of cells undergoing EndMT. Importantly, deficiency of Nox2 was associated with reduced expression of Gata4, Tgfβ2, Bmp2, Bmp4, and Snail1, which are critical to endocardial cushion and valvoseptal development. We conclude that NOX2 is critical to EndMT, endocardial cushion cell proliferation, and normal embryonic heart development.

Highlights

Congenital heart defects (CHDs) are birth defects in infants affecting about 1% of live births [1, 2]
epithelial to mesenchymal transition (EMT) is a process by which epithelial cells undergo their phenotypic transformation to become mesenchymal cells [27, 28]
Our study shows for the first time that NOX2-mediated Reactive oxygen species (ROS) signaling is critical to AV cushion endocardial to mesenchymal transition (EndMT), cell proliferation/survival, and normal heart morphogenesis (Figure 8)

Summary

Introduction

Congenital heart defects (CHDs) are birth defects in infants affecting about 1% of live births [1, 2]. An intricate network of signaling molecules and transcription factors in the epicardium, myocardium, and endocardium regulates cardiac morphogenesis [5]. Reactive oxygen species (ROS) are important signaling molecules that modulate the intracellular redox state and gene expression profiles to regulate cell proliferation, differentiation, apoptosis, and migration [10, 11]. An imbalance in ROS production may have adverse effects on fetal development [12, 13] To this end, we and others have shown that higher ROS levels in the embryonic heart alter gene expression profile and result in a wide range of CHDs, suggesting that overproduction of ROS disturbs normal heart development [14,15,16]

Methods

Results

Conclusion