De Bartolo Anna, Rago Vittoria, Romeo Naomi, De Cicco Marika, Lefranc Benjamin, Leprince Jérôme, Passarino Giuseppe, Pagliaro Pasquale, Anouar Youssef, Rocca Carmine, Angelone Tommaso
Cellular and Molecular Cardiovascular Physiology and Pathophysiology Laboratory, Department of Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, Rende, CS, Italy.
Human Anatomy Laboratory, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, CS, Italy.
Geroscience. 2025 Jul 1. doi: 10.1007/s11357-025-01759-7.
Cellular senescence is a key driver of heart disease, yet its regulation in cardiomyocytes remains poorly understood. Selenoprotein T (SELENOT) plays a crucial role in cardiomyocyte differentiation and protection, but its role in cardiomyocyte senescence remains unknown. Here, we explore the novel role of SELENOT in preserving cardiomyocyte viability and genomic integrity during doxorubicin-induced senescence. Senescent differentiated cardiomyocytes exhibit hallmarks of cellular senescence, including increased β-galactosidase activity and elevated p53 and p21 levels, and upregulation of senescence-associated secretory phenotype (SASP) markers (i.e. MMP3, IL6, and TNFα). Additionally, senescent cells displayed disrupted cytosolic and mitochondrial redox homeostasis, which were mitigated by PSELT (a small peptide that mimics SELENOT activity). Notably, PSELT positively influenced DNA damage markers (p-γH2AX and lamin B1) and prevented ER stress regulating BIP, calnexin, IRE1α, and ERO1α expression. Intriguingly, SELENOT expression was upregulated in response to senescence, suggesting a stress-sensing redoxin function. Loss-of-function studies revealed that SELENOT deficiency led to cardiomyocyte death and DNA damage, which were only partially rescued by PSELT, supporting the existence of cross-regulatory mechanisms within the SELENOT/PSELT axis. Mechanistically, similar to SSO, an irreversible inhibitor of CD36, PSELT mitigated the senescence-induced upregulation of CD36, a key player in cardiac aging. Co-immunoprecipitation analysis demonstrated that SELENOT interacts with CD36 in both normal and senescent human cardiomyocytes. Overall, these findings underscore the essential role of SELENOT in preserving the viability and genomic integrity of senescent human cardiomyocytes and suggest that PSELT-mediated inhibition of CD36 may represent a promising therapeutic strategy for treating age-related cardiac dysfunction.
细胞衰老在心脏病发生中起关键作用，但其在心肌细胞中的调控机制仍不清楚。硒蛋白T（SELENOT）在心肌细胞分化和保护中起关键作用，但其在心肌细胞衰老中的作用尚不清楚。在此，我们探讨SELENOT在阿霉素诱导的衰老过程中维持心肌细胞活力和基因组完整性的新作用。衰老的分化心肌细胞表现出细胞衰老的特征，包括β-半乳糖苷酶活性增加、p53和p21水平升高以及衰老相关分泌表型（SASP）标志物（即MMP3、IL6和TNFα）上调。此外，衰老细胞的胞质和线粒体氧化还原稳态被破坏，而PSELT（一种模拟SELENOT活性的小肽）可缓解这种破坏。值得注意的是，PSELT对DNA损伤标志物（p-γH2AX和核纤层蛋白B1）有积极影响，并阻止内质网应激调节BIP、钙连接蛋白、IRE1α和ERO1α的表达。有趣的是，SELENOT的表达随着衰老而上调，提示其具有应激感应氧化还原功能。功能缺失研究表明，SELENOT缺乏导致心肌细胞死亡和DNA损伤，PSELT只能部分挽救这些损伤，这支持了SELENOT/PSELT轴内存在交叉调节机制。机制上，与CD36的不可逆抑制剂SSO类似，PSELT减轻了衰老诱导的CD36上调，CD36是心脏衰老的关键因子。免疫共沉淀分析表明，SELENOT在正常和衰老的人类心肌细胞中均与CD36相互作用。总体而言，这些发现强调了SELENOT在维持衰老人类心肌细胞活力和基因组完整性中的重要作用，并表明PSELT介导的CD36抑制可能是治疗年龄相关心脏功能障碍的一种有前景的治疗策略。
