Long noncoding RNA Cfast regulates cardiac fibrosis

Area of Science:

• Cardiovascular Biology
• Molecular Biology
• RNA Biology

Background:

• Cardiac fibrosis is a hallmark of heart disease, impairing heart function and leading to heart failure.
• Long noncoding RNAs (lncRNAs) are emerging regulators, but their role in cardiac fibrosis remains largely unknown.

Purpose of the Study:

• To identify and characterize novel lncRNAs involved in cardiac fibrosis.
• To elucidate the functional role and molecular mechanism of a specific lncRNA, Cfast, in cardiac fibroblast activation and fibrosis.

Main Methods:

• Unbiased transcriptome profiling in a mouse model of myocardial infarction (MI).
• Silencing of Cfast using small interfering RNAs (siRNAs) and short hairpin RNAs (shRNAs).
• Assessment of fibrosis-related gene expression, myofibroblast transdifferentiation, cardiac fibrosis, and cardiac function.
• RNA pull-down and mass spectrometry to identify Cfast interacting proteins.

Main Results:

• Identified Cfast, a cardiac fibroblast-enriched lncRNA, significantly upregulated after MI.
• Cfast silencing suppressed fibrosis markers, myofibroblast activation, and attenuated cardiac fibrosis in vivo.
• Inhibition of Cfast ameliorated cardiac function post-injury.
• Discovered COTL1 as a Cfast interacting protein, revealing a mechanism involving TGF-β signaling enhancement.

Conclusions:

• Cfast is a novel lncRNA that promotes cardiac fibroblast activation and fibrosis.
• Cfast regulates fibrosis by modulating the COTL1-TRAP1 interaction and enhancing TGF-β signaling.
• Cfast represents a potential therapeutic target for treating cardiac fibrosis and related heart diseases.