The Dual Role of NOX4 in Cardiovascular Diseases: Driver of Oxidative Stress and Mediator of Adaptive Remodeling.

Abstract

NADPH oxidase 4 (NOX4) plays a crucial role in regulating cardiac function and pathology through its involvement in oxidative stress, fibrosis, and maladaptive remodeling. Studies have demonstrated that NOX4 is upregulated in response to various cardiovascular stressors, including heart failure, myocardial infarction, arrhythmias, and diabetes. This upregulation contributes to detrimental processes like fibrosis, hypertrophy, and inflammation, which are hallmarks of cardiovascular diseases. Inhibition or knockout of NOX4 has shown promise in mitigating these pathological changes, suggesting that NOX4 represents a potential therapeutic target for treating heart disease. However, NOX4's role is not entirely negative. It also plays a protective role in the heart, supporting myocardial remodeling and angiogenesis and regulating cardiac energy metabolism. Its constitutive ROS production and ability to respond to environmental cues like hypoxia help maintain cellular homeostasis and facilitate adaptive responses to stress. The impact of NOX4 on cardiac health depends not only on its expression level but also on the nature of the stress, the duration of activation, and the balance between protective signaling and oxidative injury. Collectively, the findings suggest that NOX4 functions as a redox sensor, modulating cellular responses to fluctuations in oxidative stress by signaling the need to re-establish redox homeostasis. The ultimate impact of cardiac NOX4 activity, whether protective or deleterious, is highly context-dependent and should not be evaluated through a singular interpretative framework. In conclusion, NOX4 is a dual-function enzyme that can both exacerbate and protect against cardiac pathology, making it a promising, though complex, therapeutic target for various cardiovascular diseases.