A circular RNA derived from the ryanodine receptor 2 locus controls cardiac hypertrophy and calcium handling

作者：Wen Pan, Hannah Jill Hunkler, Shambhabi Chatterjee, Dongchao Lu, Isabelle Riedel, Anika Gietz, Ke Xiao, Maximilian Fuchs, Dimyana Neufeldt, Theresia Kraft, Cheng-Kai Huang, Sarah Cushman, Anne Bührke, Arne Schmidt, Elisa Mohr, Natalie Weber, Christian Bär, Thomas Thum · 发表于：Cellular and Molecular Life Sciences · 年份：2025 · DOI：10.1007/s00018-025-05915-2 · 被引用次数：3 · 研究领域：Circular RNAs in diseases、MicroRNA in disease regulation、RNA regulation and disease

Abstract Heart failure (HF) is a leading cause of mortality worldwide, characterized by structural and functional alterations that result in reduced cardiac function. During the progression of HF, cardiomyocytes undergo profound remodeling – including development of pathological hypertrophy and impaired calcium handling – which exacerbates cardiac dysfunction. Given the limited efficacy of current pharmacological treatments, there is an urgent need for novel mechanistically-orientated therapeutic strategies. Circular RNAs (circRNAs), a recently identified sub-class of non-coding RNAs, have emerged as pivotal regulators of diverse cellular processes in homeostasis and disease. We identified a significant repression of circRYR2 (mmu_circ_0000431), derived from the ryanodine receptor 2 (RYR2) locus, through global RNA profiling in hypertrophic compared to healthy murine hearts. Notably, a decreased expression of the human circRYR2 homologue hsa_circ_0112647 was also found in human failing hearts. Loss-of-function experiments in murine and human cardiomyocytes resulted in hypertrophic responses, whereas AAV-based overexpression of circRYR2 prevented cytokine-induced cardiomyocyte hypertrophy. Whole transcriptome analysis after circRYR2 depletion identified massive perturbations of calcium handling and contractility pathways. Indeed, modulation of circRYR2 affected the expression of the sarco/endoplasmic reticulum Ca²⁺ ATPase 2a (SERCA2a), and consequently, Ca 2+ transients were a...