Abstract 13074: NADPH Oxidase 4 Mediates Cardiac Fibrosis and Hypertrophy through Activating Akt/mTOR and NF[[Unable to Display Character: ]]b Signaling Pathways
Rationale: Left ventricle remodeling is a common response to many forms of chronic cardiac injury eventually leading to heart failure. NADPH oxidase 4 (Nox4) is a major source of reactive oxygen spices (ROS) in the heart. Nox4 expression has been implicated in cardiac remodeling, but the precise role of Nox4 remains controversial. Furthermore, Nox4-derived ROS-targeting effector signals in the myocardium remain unknown.
Objective: We investigated the role of Nox4 in cardiac remodeling and explore potential mechanisms by which Nox4 mediates its effects.
Methods and Results: Cardiac specific human Nox4 transgenic mice (c-hNox4 Tg) were generated. Four groups of mice were studied: 1) control mice (CTL): littermates that are Cre positive but negative for hNox4 transgene; 2) c-hNox4 Tg mice; 3) angiotensin II-infused CTL mice and 4) AngII-infused c-hNox4 Tg mice. The c-hNox4 Tg mice exhibited a 10-fold increase in Nox4 protein expression and 8-fold increase in the production of ROS. These mice also exhibited cardiac remodeling, manifested as interstitial fibrosis without significant myocyte hypertrophy compared to CTL mice. Continuous infusion of AngII to CTL mice increased cardiac Nox4 expression and induced fibrosis as well as hypertrophy. AngII-infusion to hNox4 Tg mice exhibited advanced cardiac remodeling and robust elevation in cardiac hNox4 expression, indicating that AngII synergistically worsens cardiac injury, by enhancing Nox4 expression. There was no change in the levels of other NADPH oxidases. Moreover, cardiomyocyte Nox4 transgene- and/or AngII-infusion induced reactivation of fetal cardiac genes, characteristic of cardiomyocyte injury and significantly activated the Akt-mTOR and NF[[Unable to Display Character: ]]b signaling pathways. Treatment of mice with the GKT137831, an inhibitor of Nox4/Nox1, abolished the increase in ROS and prevented cardiac remodeling while suppressing Akt-mTOR and NF[[Unable to Display Character: ]]b signaling pathway.
Conclusions: Excessive cardiac specific expression of Nox4 causes cardiac remodeling, through activation Akt-mTOR and NF[[Unable to Display Character: ]]b signaling pathways. This study suggests that excess Nox4 in the heart is therapeutic target and inhibition of Nox4 by GKT137831 has therapeutic potential to prevent/treat cardiac remodeling and potentially heart failure.
- © 2013 by American Heart Association, Inc.