Bianchi Marzia, Panera Nadia, Petrillo Sara, Cicolani Nicolò, De Stefanis Cristiano, Scarsella Marco, Ciavardelli Domenico, Piemonte Fiorella, Alisi Anna, Pastore Anna
Research Unit of Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy.
Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy.
Antioxidants (Basel). 2025 Aug 28;14(9):1059. doi: 10.3390/antiox14091059.
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 gene in H9c2 rat cardiomyoblasts. We observed that PPARα silencing induces a hypertrophic phenotype, characterized by increased and decreased 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.
脂质激活核受体的过氧化物酶体增殖物激活受体家族（PPARs）在细胞脂质代谢调节中起关键作用。在心肌中，PPARα高度表达并调节参与脂肪酸氧化的基因，但其活性在肥厚型心脏中下调；然而，慢性PPARα缺乏对心脏收缩装置的影响仍不清楚。本研究旨在探讨PPARα在肥厚型表型中的作用，并评估抗氧化剂依布硒啉（Ebs）治疗对与PPARα缺失相关变化的潜在影响。因此，我们通过稳定沉默H9c2大鼠心肌成纤维细胞中的基因，建立了心脏肥大的体外模型。我们观察到PPARα沉默诱导了一种肥厚型表型，其特征为增加和减少的表达、线粒体失调、脂质代谢受损、氧化应激和铁死亡相关改变。在表观遗传学上，H3K27ac水平升高而H3K27me3水平降低。此外，miR-34a、miR-132和miR-331下调，提示在PPARα相关的心脏肥大中存在miRNA介导的机制。用Ebs治疗，一种对铁死亡和表观遗传学有抑制作用的氧化还原活性化合物，可逆转肥厚型表型并恢复miRNA水平。总之，我们发现PPARα缺失促进氧化应激和肥厚型表型，并且Ebs可能作为一种潜在的治疗剂。
