Targeting the highly abundant circular RNA circSlc8a1 in cardiomyocytes attenuates pressure overload induced...

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Non-coding RNA Research

Background:

• Circular RNAs (circRNAs) are increasingly recognized in cardiac biology, but their functional roles, particularly in cardiomyocytes, require further elucidation.
• circSlc8a1, a highly abundant circRNA in the heart, originates from the sodium-calcium exchanger gene (Slc8a1).
• The functional significance of abundant cardiomyocyte circRNAs, including circSlc8a1, remains largely unexplored.

Purpose of the Study:

• To investigate the functional role of the highly abundant cardiomyocyte circRNA, circSlc8a1, in the heart.
• To determine if circSlc8a1 interacts with and regulates microRNAs involved in cardiac function.
• To explore the potential of circSlc8a1 as a therapeutic target for cardiac hypertrophy.

Main Methods:

• A microRNA (miRNA) screen was conducted using RNA from endogenous cardiomyocyte circSlc8a1 pull-downs.
• Luciferase assays and reciprocal pull-down assays were employed to validate the interaction between circSlc8a1 and miR-133a.
• In vivo studies utilized AAV9-mediated RNAi knockdown and cardiomyocyte-specific overexpression of circSlc8a1 in pressure-overload models.

Main Results:

• MicroRNA-133a (miR-133a) was significantly enriched in circSlc8a1 pull-down fractions, indicating a potential interaction.
• Knockdown of circSlc8a1 attenuated pressure-overload-induced cardiac hypertrophy, while its overexpression led to heart failure.
• circSlc8a1 was shown to regulate miR-133a targets, including SRF, CTGF, ADRB1, and ADCY6.

Conclusions:

• circSlc8a1 functions as an endogenous 'sponge' for miR-133a within cardiomyocytes.
• circSlc8a1 plays a critical role in regulating cardiac hypertrophy.
• circSlc8a1 represents a promising novel therapeutic target for managing cardiac hypertrophy.