Paraspeckles as a target for myocardial hypertrophy

Area of Science:

• Cardiovascular Biology
• RNA Biology
• Cellular Stress Response

Background:

• Pathological cardiac hypertrophy precedes heart failure (HF) and can be triggered by stimuli like pressure overload.
• Liquid-liquid phase separation (LLPS) is a cellular stress response mechanism, but its role in HF is unknown.
• Paraspeckles, formed by Neat1 long non-coding RNA (lncRNA) via LLPS, are of interest in HF pathogenesis.

Purpose of the Study:

• Investigate the role of Neat1-mediated LLPS in cardiac hypertrophy and HF.
• Determine if targeting paraspeckles can prevent pathological cardiac remodelling.

Main Methods:

• Assessed paraspeckle presence in cardiomyocytes using RNA fluorescence in situ hybridization (FISH) under stress and in human HF samples.
• Quantified Neat1 expression in human HF.
• Utilized Neat1 knockout mice and knockdown models for loss-of-function studies.
• Explored therapeutic potential by disrupting paraspeckle formation in a mouse model of HF.

Main Results:

• Paraspeckles, mediated by Neat1 lncRNA, were upregulated in cardiomyocytes under stress and in human HF.
• Disrupting paraspeckles attenuated cardiomyocyte remodelling; Neat1 ablation prevented cardiac dysfunction.
• Neat1-driven LLPS promoted cardiac remodelling by inducing ferroptosis via nuclear sequestration of Fth1 mRNA.
• Cardiomyocyte-specific Neat1 knockdown prevented heart failure development in mice.

Conclusions:

• LLPS driven by Neat1 lncRNA promotes pressure-overload cardiac remodelling by regulating iron homeostasis.
• Targeting Neat1-mediated LLPS offers a novel RNA-based therapeutic approach for preventing cardiac remodelling and HF.