Circulation Research | Role of Nonmuscle α-Actinin 4 in Cardiac Remodeling

This study is the first to reveal the role of nonmuscle α-actinin-4 (ACTN4) in cardiac Z-discs, demonstrating its critical functions in regulating cardiomyocyte cytoskeletal remodeling, myocardial contractility, and cardiac remodeling. Aberrant ACTN4 expression is linked to the risk of heart failure, providing new molecular targets for cardiac disease research.

 

Literature Overview

The article, titled 'Nonmuscle α-Actinin-4 Couples Sarcomere Function to Cardiac Remodeling,' published in Circulation Research, reviews and summarizes the expression of ACTN4 in cardiomyocytes and its impact on cardiac structure and function. The study systematically analyzes the role of ACTN4 in cardiac remodeling using iPSC-derived cardiomyocytes, zebrafish embryonic models, and mouse models. By integrating gene expression, structural modeling, and functional validation, the research reveals ACTN4's key regulatory role in cardiac contractility and remodeling.

Background Knowledge

Cardiac remodeling is an adaptive response to long-term cardiac stress or disease states, involving mechanisms such as cytoskeletal remodeling, regulation of contractility, and cellular hypertrophy. ACTN4 belongs to the α-actinin family, typically highly expressed in nonmuscle cells, yet its function in the heart remains unclear. Traditionally, Z-discs are thought to be regulated by muscle-specific ACTN2, not ACTN4. However, this study challenges this paradigm by showing that ACTN4 can form heterodimers with ACTN2 and jointly contribute to Z-disc structural stability. The study further explores the role of ACTN4 in cardiomyocyte contractile function and evaluates its genetic association with cardiac diseases such as HFpEF. These findings provide new insights into the molecular mechanisms of cardiac remodeling and suggest that ACTN4 could serve as a potential therapeutic target or biomarker.

 

 

Research Methods and Experiments

The research team confirmed that ACTN4 expression in human cardiomyocytes is comparable to or exceeds that of MYH6 by comparing the expression levels of nonmuscle and muscle-specific cytoskeletal proteins. Immunoprecipitation and structural modeling were used to analyze the interaction between ACTN4 and ACTN2, while siRNA knockdown, overexpression, and pharmacological interventions were employed to modulate ACTN4 function. Its impact on sarcomere assembly, contractility, and cellular hypertrophy was evaluated in iPSC-derived cardiomyocytes. In zebrafish embryos, ACTN4 was knocked out using morpholino or CRISPR/Cas9 technology to observe phenotypes such as ventricular hypercontractility and atrial enlargement. Contractility was pharmacologically modulated to validate the causal relationship of ACTN4 in cardiac remodeling. In mouse models, the expression dynamics of ACTN4 under left ventricular pressure overload were examined. Additionally, the BioVU biobank was utilized to analyze the association between ACTN4 gene polymorphisms and HFpEF risk, while meta-analyses assessed ACTN4 expression patterns in cardiomyopathies.

Key Conclusions and Perspectives

• ACTN4 localizes to the Z-discs of ventricular tissues in humans, mice, and zebrafish and forms complexes with ACTN2.
• ACTN4 knockdown leads to increased sarcomere assembly, reduced turnover of sarcomere components, enhanced contractility, and contractility-dependent cellular hypertrophy.
• ACTN4 overexpression inhibits sarcomere assembly, and its actin-binding domain fusion protein can block contractility.
• In zebrafish, ACTN4 knockout results in ventricular hypercontractility and atrial enlargement; modulating contractility can mimic or reverse these phenotypes.
• Mouse models show upregulation of ACTN4 under left ventricular pressure overload, with no change in ACTN2 levels.
• Among 14 ACTN4 SNPs, one is associated with reduced HFpEF risk, and meta-analyses support the upregulation pattern of ACTN4 in cardiomyopathy.

Research Significance and Prospects

ACTN4, a nonmuscle α-actinin, has been newly identified to regulate cardiac Z-disc structure and contractility. Its expression changes are linked to cardiac remodeling, suggesting its potential as a biomarker or therapeutic target for heart failure. Future research should further explore the molecular mechanisms of ACTN4 in cardiac remodeling and evaluate the association between its genetic variants and clinical phenotypes in human heart diseases.

 

 

Conclusion

This study unveils the function of nonmuscle α-actinin ACTN4 in cardiac Z-discs and systematically evaluates its role in regulating cardiomyocyte contractility and cardiac remodeling. Changes in ACTN4 expression are associated with enhanced cardiac contractility, sarcomere stability, and cellular hypertrophy, and its relevance to cardiac remodeling is observed in both mouse and human disease models. These findings provide a new molecular mechanism for ACTN4 function in cardiac diseases and lay a theoretical foundation for developing therapeutic targets for HFpEF and cardiomyopathy. The study also suggests that genetic variations in ACTN4 may affect cardiac function, warranting further investigation into its regulatory network in cardiac remodeling and its translational potential in clinical applications.

 

James B Hayes, Dharmendra Choudhary, Dylan Ritter, Ela W Knapik, and Dylan T Burnette. Nonmuscle α-Actinin-4 Couples Sarcomere Function to Cardiac Remodeling. Circulation Research.