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Antioxidants
Volume 14
Issue 9
10.3390/antiox14091059
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Peroxisome Proliferator-Activated Receptor Family of Lipid-Activated Nuclear Receptors Alpha Silencing Promotes Oxidative Stress and Hypertrophic Phenotype in Rat Cardiac Cells

by
Marzia Bianchi
1,
Nadia Panera
1,
Sara Petrillo
2,
Nicolò Cicolani
3,
Cristiano De Stefanis
3,
Marco Scarsella
3,
Domenico Ciavardelli
4,
Fiorella Piemonte
2,
Anna Alisi
1,* and
Anna Pastore
1
1
Research Unit of Genetics of Complex Phenotypes, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy
2
Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
3
Core Facilities, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy
4
School of Medicine and Surgery, University “Kore” of Enna, 94100 Enna, Italy
*
Author to whom correspondence should be addressed.
Antioxidants 2025, 14(9), 1059; https://doi.org/10.3390/antiox14091059 (registering DOI)
Submission received: 31 July 2025 / Revised: 21 August 2025 / Accepted: 27 August 2025 / Published: 28 August 2025
(This article belongs to the Special Issue The Janus Face of Oxidative Stress in Normal and Pathological Conditions)
Versions Notes

Abstract

The peroxisome proliferator-activated receptor family of lipid-activated nuclear receptors (PPARs) plays a critical role in the regulation of cellular lipid metabolism. In cardiac muscle, PPARα is highly expressed and regulates genes involved in fatty acid oxidation, but its activity is downregulated in hypertrophic hearts; however, the consequences of chronic PPARα deficiency on the cardiac contractile apparatus remain unclear. This study aimed to investigate the PPARα role in hypertrophic phenotype and to evaluate the potential effects of the antioxidant Ebselen (Ebs) treatment on changes associated with PPARα depletion. We thus generated an in vitro model of cardiac hypertrophy by stable silencing of the PPARA gene in H9c2 rat cardiomyoblasts. We observed that PPARα silencing induces a hypertrophic phenotype, characterized by increased NPPB and decreased FBXO32 expression, mitochondrial dysregulation, impaired lipid metabolism, oxidative stress, and ferroptosis-related alterations. Epigenetically, H3K27ac levels increased while H3K27me3 decreased. Moreover, miR-34a, miR-132, and miR-331 were downregulated, implicating a miRNA-mediated mechanism in PPARα-linked cardiac hypertrophy. Treatment with Ebs, a redox-active compound with inhibitory effects on ferroptosis and epigenetics, reversed hypertrophic phenotype and restored miRNA levels. In conclusion, we found that PPARα depletion promotes oxidative stress and hypertrophic phenotype and that Ebs may act as a potential therapeutic agent.
Keywords: PPARα; ROS; Ebselen; cardiac hypertrophy PPARα; ROS; Ebselen; cardiac hypertrophy

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MDPI and ACS Style

Bianchi, M.; Panera, N.; Petrillo, S.; Cicolani, N.; De Stefanis, C.; Scarsella, M.; Ciavardelli, D.; Piemonte, F.; Alisi, A.; Pastore, A. Peroxisome Proliferator-Activated Receptor Family of Lipid-Activated Nuclear Receptors Alpha Silencing Promotes Oxidative Stress and Hypertrophic Phenotype in Rat Cardiac Cells. Antioxidants 2025, 14, 1059. https://doi.org/10.3390/antiox14091059

AMA Style

Bianchi M, Panera N, Petrillo S, Cicolani N, De Stefanis C, Scarsella M, Ciavardelli D, Piemonte F, Alisi A, Pastore A. Peroxisome Proliferator-Activated Receptor Family of Lipid-Activated Nuclear Receptors Alpha Silencing Promotes Oxidative Stress and Hypertrophic Phenotype in Rat Cardiac Cells. Antioxidants. 2025; 14(9):1059. https://doi.org/10.3390/antiox14091059

Chicago/Turabian Style

Bianchi, Marzia, Nadia Panera, Sara Petrillo, Nicolò Cicolani, Cristiano De Stefanis, Marco Scarsella, Domenico Ciavardelli, Fiorella Piemonte, Anna Alisi, and Anna Pastore. 2025. "Peroxisome Proliferator-Activated Receptor Family of Lipid-Activated Nuclear Receptors Alpha Silencing Promotes Oxidative Stress and Hypertrophic Phenotype in Rat Cardiac Cells" Antioxidants 14, no. 9: 1059. https://doi.org/10.3390/antiox14091059

APA Style

Bianchi, M., Panera, N., Petrillo, S., Cicolani, N., De Stefanis, C., Scarsella, M., Ciavardelli, D., Piemonte, F., Alisi, A., & Pastore, A. (2025). Peroxisome Proliferator-Activated Receptor Family of Lipid-Activated Nuclear Receptors Alpha Silencing Promotes Oxidative Stress and Hypertrophic Phenotype in Rat Cardiac Cells. Antioxidants, 14(9), 1059. https://doi.org/10.3390/antiox14091059

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