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

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, Ca²⁺ transients were assessed, revealing impaired or improved Ca²⁺ handling after circRYR2 knockdown or overexpression, respectively. In summary, the findings presented here provide new mechanistic insights for the circular RNA transcript derived from RYR2 locus and support circRYR2 overexpression strategies as promising therapeutic strategies for cardiac dysfunction.