Both cardiomyocyte and endothelial cell Nox4 mediate protection against hemodynamic overload-induced remodelling.

Min Zhang,Ajay M Shah,Ralf P Brandes,Heloise Mongue-Din,Katrin Schröder,Xiaohong Zhang,Norman Catibog,Daniel Martin,Ioannis Smyrnias,Bin Yu,Minshu Wang

doi:10.1093/cvr/cvx204

Min Zhang, Ajay M Shah + Show 9 more

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https://doi.org/10.1093/cvr/cvx204

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Abstract

AimsNADPH oxidase-4 (Nox4) is an important reactive oxygen species (ROS) source that is upregulated in the haemodynamically overloaded heart. Our previous studies using global Nox4 knockout (Nox4KO) mice demonstrated a protective role of Nox4 during chronic abdominal aortic banding, involving a paracrine enhancement of myocardial capillary density. However, other authors who studied cardiac-specific Nox4KO mice reported detrimental effects of Nox4 in response to transverse aortic constriction (TAC). It has been speculated that these divergent results are due to cell-specific actions of Nox4 (i.e. cardiomyocyte Nox4 detrimental but endothelial Nox4 beneficial) and/or differences in the model of pressure overload (i.e. abdominal banding vs. TAC). This study aimed to (i) investigate whether the effects of Nox4 on pressure overload-induced cardiac remodelling vary according to the pressure overload model and (ii) compare the roles of cardiomyocyte vs. endothelial cell Nox4.Methods and resultsGlobal Nox4KO mice subjected to TAC developed worse cardiac remodelling and contractile dysfunction than wild-type littermates, consistent with our previous results with abdominal aortic banding. Next, we generated inducible cardiomyocyte-specific Nox4 KO mice (Cardio-Nox4KO) and endothelial-specific Nox4 KO mice (Endo-Nox4KO) and studied their responses to pressure overload. Both Cardio-Nox4KO and Endo-Nox4KO developed worse pressure overload-induced cardiac remodelling and dysfunction than wild-type littermates, associated with significant decrease in protein levels of HIF1α and VEGF and impairment of myocardial capillarization.ConclusionsCardiomyocyte as well as endothelial cell Nox4 contributes to protection against chronic hemodynamic overload-induced cardiac remodelling, at least in part through common effects on myocardial capillary density.

Highlights

Increased production of reactive oxygen species (ROS) is involved in cardiac responses to hemodynamic stress but different ROS sources have varying roles
Our results conclusively demonstrate that both cardiomyocyte and endothelial NADPH oxidase (Nox)[4] are capable of mediating protection against chronic pressure overload-induced cardiac remodelling in the mouse heart, at least in part through common mechanisms
To establish whether the role of Nox[4] is similar in response to transverse aortic constriction (TAC) as previously observed during abdominal aortic banding (AAB), TAC was performed in global Nox4 knockout (Nox4KO) and matched WT mice

Summary

Introduction

Increased production of reactive oxygen species (ROS) is involved in cardiac responses to hemodynamic stress but different ROS sources have varying roles. Unlike sources such as mitochondria, uncoupled nitric oxide synthases, and xanthine oxidases, the NADPH oxidase (Nox) family of enzymes produce ROS as their primary function.[1] Nox proteins are especially important in redox signalling as opposed to non-specific oxidative damage.[2] Of the seven known mammalian Nox isoforms (Nox[1,2,3,4,5] and Duox1-2), Nox[2] ( known as gp91phox) and Nox[4] are the major ones in the heart. Overwhelming evidence indicates that Nox[2] is involved in the development of cardiac hypertrophy, remodelling, arrhythmia, myocyte death, and fibrosis induced by diverse disease stimuli.[3] The role of Nox[4] in the heart, is controversial. Using mice with a global knockout of Nox[4] (Nox4KO) and cardiomyocyte-targeted Nox4-overexpressing

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