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

Abstract

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 PPARα 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 PPARα 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 PPARα downregulation, was enhanced in PPARα−/− mice and prevented in Nox2−/− mice. Detailed transcriptomic analysis revealed significantly altered expression of genes relating to PPARα, oxidative stress and hypertrophy pathways in wild-type hearts, which were unaltered in Nox2−/− hearts, whilst oxidative stress pathways remained dysregulated in PPARα−/− hearts following TAC. Network analysis indicated that Nox2 was essential for PPARα downregulation in this setting and identified preferential inflammatory pathway modulation and candidate cytokines as upstream Nox2-sensitive regulators of PPARα signalling. Together, these data suggest that Nox2 is a critical driver of PPARα downregulation leading to maladaptive LVH.

Oxidative stress in cardiac hypertrophy: From molecular mechanisms to novel therapeutic targets

“…Moreover, the above abnormalities were abrogated in NOX2-KO hearts, highlighting NOX2 as a key mediator of obesity-induced cardiac hypertrophy. Although the effect of NOX2-KO on cardiac function was not investigated in this study, but in another study improved cardiac systolic function has been observed in NOX2 -/mice in the setting of pressure overload [15]. It therefore appears that dysregulated NOX2 expression is a common determinant of both obesity-and pressure-induced cardiac hypertrophy.…”

“…Dysregulated expression of NOX proteins has been proposed to contribute to the development of cardiac hypertrophy and cardiac dysfunction. Consistently, elevated levels of NOX2 have been associated with worsening systolic function by a mechanism involving downregulation of PPARα [15], an effect that could be reversed with PPARα activator fenofibrate or NOX2 inhibitor VAS2870. In the same study, transcriptomic analysis of PPARα -/mice subjected to pressure overload revealed alterations in oxidative stress and inflammatory pathways that overlapped with wild-type mice (also subjected to pressure overload), while NOX2 -/mice subjected to pressure overload exhibited minimal changes in these pathways.…”

Untangling the Cooperative Role of Nuclear Receptors in Cardiovascular Physiology and Disease

“…In hypertensive rats treated with the PPARα agonist medium-chain triglyceride tricaprylin, PPARα activation reduced cardiac oxidative stress without affecting blood pressure [140]. More recently, Harvey and colleagues showed that phenylephrine-induced hypertrophy in H9c2 cardiomyocytes reduces PPARα expression while increasing NOX2 expression and activity [141]. In line with this finding, NOX2 expression was upregulated in PPARα-null mice subjected to transverse aortic constriction (TAC), suggesting that NOX2 signaling initiates PPARα downregulation during cardiac hypertrophy.…”

Dapagliflozin Mediates Plin5/PPARα Signaling Axis to Attenuate Cardiac Hypertrophy

“…Numerous studies ( Zhao et al, 2017 ) have reported the beneficial effect of activation of the PPARα signal on the development of cardiac hypertrophy, which may be attributed to its regulation of myocardial function and energy metabolism through modulating fatty acid oxidation. Hrvey ( Harvey et al, 2020 ) reported that Nox2 was a key signaling molecule in the pathological reaction of PPARα down-regulation leading to cardiac hypertrophy, which proved that the molecular mechanism of PPARα in cardiac hypertrophy from the negative side. In cardiac hypertrophy, the overexpression of PPARα in cardiac tissue can mediate the p53/GSK3β signaling pathway to significantly improve myocardial energy deficiency and cardiac function, which also supports the important role of PPARα in the pathological process of cardiac hypertrophy ( Rana et al, 2019 ).…”