Downregulation of PPARα during Experimental Left Ventricular Hypertrophy is Critically Dependent on Nox2 NADPH Oxidase Signalling

Pressure overload-induced left ventricular hypertrophy (LVH) is initially adaptive but ultimately promotes systolic dysfunction and chronic heart failure. Whilst underlying pathways are incompletely understood, increased reactive oxygen species generation from Nox2 NADPH oxidases, and metabolic remodelling, largely driven by PPAR alpha downregulation, are separately implicated. Here, we investigated interaction between the two as a key regulator of LVH using in vitro, in vivo and transcriptomic approaches. Phenylephrine-induced H9c2 cardiomyoblast hypertrophy was associated with reduced PPAR alpha expression and increased Nox2 expression and activity. Pressure overload-induced LVH and systolic dysfunction induced in wild-type mice by transverse aortic constriction (TAC) for 7 days, in association with Nox2 upregulation and PPAR alpha downregulation, was enhanced in PPAR alpha(-/-)mice and prevented in Nox2(-/-)mice. Detailed transcriptomic analysis revealed significantly altered expression of genes relating to PPAR alpha, oxidative stress and hypertrophy pathways in wild-type hearts, which were unaltered in Nox2(-/-)hearts, whilst oxidative stress pathways remained dysregulated in PPAR alpha(-/-)hearts following TAC. Network analysis indicated that Nox2 was essential for PPAR alpha downregulation in this setting and identified preferential inflammatory pathway modulation and candidate cytokines as upstream Nox2-sensitive regulators of PPAR alpha signalling. Together, these data suggest that Nox2 is a critical driver of PPAR alpha downregulation leading to maladaptive LVH.