A Novel Circular RNA circITGa9 Predominantly Generated in Human Heart Disease Induces Cardiac Remodeling and Fibrosis

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Genomics

Background:

• Circular RNAs (circRNAs) are increasingly recognized for their roles in cardiovascular diseases.
• Cardiac hypertrophy is associated with significant changes in gene expression, including circRNAs.

Purpose of the Study:

• To identify novel circRNAs involved in cardiac hypertrophy.
• To investigate the role of circITGa9 in cardiac fibrosis and remodeling.
• To explore circITGa9 as a potential therapeutic target for cardiovascular diseases.

Main Methods:

• High-throughput circRNA sequencing of normal and hypertrophic myocardial tissues.
• Validation of circRNA expression in patient cohorts.
• In vivo studies using mouse models of cardiac hypertrophy (transverse aortic constriction).
• Biochemical assays to identify circRNA-binding proteins and interaction sites.
• Development of therapeutic strategies targeting circITGa9.

Main Results:

• Discovery of 32,034 novel circRNAs with distinct cardiac expression patterns.
• Significant upregulation of circITGa9 in cardiac hypertrophy patients and validated in extensive sample pools.
• circITGa9 injection exacerbated cardiac fibrosis in a mouse model.
• circITGa9 binds to tropomyosin 3 (TPM3), inducing actin polymerization and fibrosis.
• Therapeutic interventions (siRNA, blocking oligos) targeting circITGa9 improved cardiac function and reduced fibrosis in vivo.

Conclusions:

• Elevated circITGa9 is a key driver of cardiac remodeling and fibrosis.
• circITGa9 represents a promising therapeutic target for mitigating cardiovascular disease progression.
• Targeting the circITGa9-TPM3 interaction offers a novel strategy for treating cardiac fibrosis.