Circular RNA circZFPM2 regulates cardiomyocyte hypertrophy and survival

Area of Science:

• Genetics
• Molecular Biology
• Cardiology

Background:

• Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease.
• Current treatments for HCM are largely symptomatic and do not fully address molecular causes.
• Circular RNAs (circRNAs) are emerging as key regulators of cellular functions.

Purpose of the Study:

• To identify novel molecular targets for HCM treatment.
• To investigate the role of circRNAs in the pathogenesis of HCM.
• To evaluate circZFPM2 as a potential therapeutic agent for cardiac hypertrophy.

Main Methods:

• Global circRNA-specific next-generation sequencing in human cardiac tissue.
• In vitro loss-of-function and gain-of-function studies in neonatal rat and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).
• Assessment of cardiomyocyte function, mitochondrial respiration, apoptosis, and gene expression.
• In vivo studies using HCM-patient-derived cardiac organoids and Multi-Omics analysis.

Main Results:

• Identified circZFPM2 (hsa_circ_0003380) as a highly conserved circRNA significantly upregulated in HCM cardiac tissue.
• Knockdown of circZFPM2 induced cardiomyocyte hypertrophy, impaired mitochondrial respiration, increased reactive oxygen species, and promoted apoptosis.
• Overexpression of circZFPM2, via lipid nanoparticles or AAV vectors, rescued hypertrophic gene expression and enhanced cell survival.
• CM-specific circZFPM2 overexpression in HCM-derived cardiac organoids improved contractility and mitochondrial function.

Conclusions:

• circZFPM2 plays a protective role against cardiac hypertrophy and dysfunction.
• circZFPM2 demonstrates potential as a novel therapeutic target for HCM and other cardiac hypertrophy conditions.
• Delivery of circZFPM2 offers a promising strategy for treating genetic cardiac disorders.