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Life Sci."],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    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 \u2013 including development of pathological hypertrophy and impaired calcium handling \u2013 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 Ca\u00b2\u207a ATPase 2a (SERCA2a), and consequently, Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transients were assessed, revealing impaired or improved Ca\n                    <jats:sup>2+<\/jats:sup>\n                    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.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s00018-025-05915-2","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T08:12:19Z","timestamp":1761034339000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A circular RNA derived from the ryanodine receptor 2 locus controls cardiac hypertrophy and calcium handling"],"prefix":"10.1007","volume":"82","author":[{"given":"Wen","family":"Pan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah J.","family":"Hunkler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shambhabi","family":"Chatterjee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongchao","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Riedel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anika","family":"Gietz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Fuchs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimyana","family":"Neufeldt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresia","family":"Kraft","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Kai","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Cushman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"B\u00fchrke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arne","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Mohr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Weber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9276-9383","authenticated-orcid":false,"given":"Christian","family":"B\u00e4r","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Thum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,21]]},"reference":[{"key":"5915_CR1","doi-asserted-by":"crossref","unstructured":"Martin SS, Aday AW, Almarzooq ZI, Anderson CAM, Arora P, Avery CL, Baker-Smith CM, Barone Gibbs B, Beaton AZ, Boehme AK, Commodore-Mensah Y, Currie ME, Elkind MSV, Evenson KR, Generoso G, Heard DG, Hiremath S, Johansen MC, Kalani R, Kazi DS, Ko D, Liu J, Magnani JW, Michos ED, Mussolino ME, Navaneethan SD, Parikh NI, Perman SM, Poudel R, Rezk-Hanna M, Roth GA, Shah NS, St-Onge MP, Thacker EL, Tsao CW, Urbut SM, Van Spall HGC, Voeks JH, Wang NY, Wong ND, Wong SS, Yaffe K, Palaniappan LP (2024) 2024 heart disease and stroke statistics. 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