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Article

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

1
Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast BT9 7AE, UK
2
Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast BT7 1NN, UK
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(12), 4406; https://doi.org/10.3390/ijms21124406
Received: 29 May 2020 / Revised: 17 June 2020 / Accepted: 18 June 2020 / Published: 20 June 2020
(This article belongs to the Section Molecular Biology)
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. View Full-Text
Keywords: Nox2 NADPH oxidase; PPARα; left ventricular hypertrophy; oxidative stress; microarray; transverse aortic constriction; chronic heart failure Nox2 NADPH oxidase; PPARα; left ventricular hypertrophy; oxidative stress; microarray; transverse aortic constriction; chronic heart failure
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MDPI and ACS Style

Harvey, A.P.; Robinson, E.; Edgar, K.S.; McMullan, R.; O’Neill, K.M.; Alderdice, M.; Amirkhah, R.; Dunne, P.D.; McDermott, B.J.; Grieve, D.J. Downregulation of PPARα during Experimental Left Ventricular Hypertrophy is Critically Dependent on Nox2 NADPH Oxidase Signalling. Int. J. Mol. Sci. 2020, 21, 4406. https://doi.org/10.3390/ijms21124406

AMA Style

Harvey AP, Robinson E, Edgar KS, McMullan R, O’Neill KM, Alderdice M, Amirkhah R, Dunne PD, McDermott BJ, Grieve DJ. Downregulation of PPARα during Experimental Left Ventricular Hypertrophy is Critically Dependent on Nox2 NADPH Oxidase Signalling. International Journal of Molecular Sciences. 2020; 21(12):4406. https://doi.org/10.3390/ijms21124406

Chicago/Turabian Style

Harvey, Adam P., Emma Robinson, Kevin S. Edgar, Ross McMullan, Karla M. O’Neill, Matthew Alderdice, Raheleh Amirkhah, Philip D. Dunne, Barbara J. McDermott, and David J. Grieve. 2020. "Downregulation of PPARα during Experimental Left Ventricular Hypertrophy is Critically Dependent on Nox2 NADPH Oxidase Signalling" International Journal of Molecular Sciences 21, no. 12: 4406. https://doi.org/10.3390/ijms21124406

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