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

Aims NADPH oxidase-4 (Nox4) is an important reactive oxygen species (ROS) source that is upregulated in the hemodynamically 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 versus TAC). This study aimed to: (1) investigate whether the effects of Nox4 on pressure overload-induced cardiac remodeling vary according to the pressure overload model; (2) compare the roles of cardiomyocyte versus endothelial cell Nox4. Methods and Results Global Nox4KO mice subjected to TAC developed worse cardiac remodeling 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 remodeling and dysfunction than wild-type littermates, associated with significant decrease in protein levels of HIF1α and VEGF and impairment of myocardial capillarization. Conclusions Cardiomyocyte as well as endothelial cell Nox4 contributes to protection against chronic hemodynamic overload-induced cardiac remodeling, at least in part through common effects on myocardial capillary density.