Clin Res Cardiol (2021). 10.1007/s00392-021-01933-9

Circular RNAs in cardiac energy metabolism

A. Schmidt1, K. Schmidt1, S. Groß1, S. Cushman1, K. Zimmer1, J. Bode1, D. LU1, K. Xiao2, A. Just1, A. Pfanne1, J. Fiedler2, M. Jung1, T. Thum1, für die Studiengruppe: IMTTS

1Institut für Molekulare und Translationale Therapiestrategien, OE-8886, Medizinische Hochschule Hannover, Hannover; 2Kardiovaskuläre Forschung, C11, Fraunhofer-Institut für Toxikologie und Experimentelle Medizin ITEM, Hannover;

Heart failure (HF) is a major cause of mortality after coronary artery diseases in the world. Chronic hypoxia is an essential pathophysiological component in many cardiac diseases. The heart switches energy metabolism efficiently to maintain the balance of energy supply and demand in the adapta-tion to chronic hypoxia. However, impaired metabolic efficiency leads to metabolism disorder, which ultimately contribute to the severity of heart failure. Therefore, targeting of the cardiac me-tabolism is an emerging therapeutic strategy to improve cardiac function. Circular RNAs (circRNAs) – a subgroup of the non-coding RNA family – are formed via a non-canonical splicing event called backsplicing and alterations of several circRNAs expression level have been shown in the progres-sion of cardiac diseases. However, the exact function of circRNAs in HF - especially during mito-chondrial dysfunction - still remains unknown. To identify circRNAs which play essential roles in the cardiac metabolism during heart failure pro-gression, RNA sequencing is performed from heart biopsy samples of healthy donors and patients with heart failure. 15,255 out of 86,406 circRNAs are found to be differentially expressed in the HF patient heart. The function of host gene, the level of sequence conservation between human and mouse genome, and RNase R digestion assay are used to validate our target circRNA. Two circRNAs, named circAS1 and circAS4, are identified as the most promising candidates for our present study. Both circRNAs are single-exon-encoded and highly conserved between human, mouse, and rat. Their cardiac expression is highly upregulated in HF patient heart compared to healthy donors. In line, our in vitro study also recaptured both circRNAs are increased in cardiomyocytes and cardiac fibroblasts upon hypoxic stress. Interestingly, reduction of both circRNA through siRNA treatment results in decreased metabolic activity as well as increased oxidative stress in cardiac fibroblasts and cardiomyocytes, while overexpression of both circRNAs via plasmid transfection rescues the meta-bolic activity. These results strongly suggest both circRNAs might play a role in metabolism regula-tion and could serve as a potential therapeutic target. However, further investigations are required to understand the underlying mechanisms of these circRNAs in cardiac energy metabolism.

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