Silencing mouse circular RNA circSlc8a1 by circular antisense cA-circSlc8a1 induces cardiac hepatopathy

Area of Science:

• Molecular Biology
• Cardiovascular Research
• RNA Biology

Background:

• Circular RNAs (circRNAs) are non-coding RNAs with critical roles in cardiovascular diseases.
• Studying circRNA function in vivo is challenging due to a lack of effective silencing methods.
• Gene editing often impacts parental coding genes, complicating circRNA-specific studies.

Purpose of the Study:

• To develop a method for specifically silencing circRNAs in vivo without affecting parental linear mRNAs.
• To investigate the functional role of circSlc8a1 in cardiac physiology and disease.
• To explore the therapeutic potential of circular antisense RNAs for cardiovascular diseases.

Main Methods:

• Development of a circular antisense RNA (cA-circSlc8a1) targeting circSlc8a1.
• Generation of transgenic mice expressing cA-circSlc8a1 for in vivo silencing.
• Generation of transgenic mice overexpressing circSlc8a1.
• Assessment of cardiac function and pathology in mouse models.
• Mitochondrial localization and ATP synthesis assays.

Main Results:

• Transgenic cA-circSlc8a1 mice exhibited congestive heart failure, characterized by increased body weight, edema, and hepatopathy.
• Overexpression of circSlc8a1 demonstrated a protective effect in a pressure overload-induced heart failure model.
• circSlc8a1 was found to translocate into mitochondria and promote ATP synthesis.
• The developed method successfully silenced circSlc8a1 without affecting the Slc8a1 linear mRNA.

Conclusions:

• circSlc8a1 plays an essential role in maintaining normal heart function.
• circSlc8a1's mitochondrial localization suggests a role in energy metabolism.
• Circular antisense RNA technology offers a specific approach for circRNA silencing in vivo.
• This study provides a foundation for developing circular antisense RNA-based gene therapies for cardiovascular diseases.