Striatin protein's role in human cardiomyocytes: Connection to electrical dysregulation and sudden cardiac death

Abstract

Striatin (Strn) is an important scaffolding protein linked to various cardiovascular diseases, including arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, and hypertrophic cardiomyopathy, as demonstrated in preclinical^1-3 studies. The use of cardiomyocytes derived from embryonic stem cells and induced pluripotent stem cells has become increasingly valuable for studying the molecular pathomechanisms underlying these cardiomyopathies. These models closely resemble human cardiomyocytes and possess the ability to differentiate into various cell^4-9 types, providing a robust platform for preclinical studies and drug screening. Despite their inherent limitations, such as the lack of hormonal or neural support, these models have successfully elucidated several channelopathies and cardiomyopathies.^4-11

Strn is characterized by four distinct protein–protein interaction domains, yet its functional role in cardiomyocytes remains inadequately explored. Notably, the specific impact of Strn on ion channel currents within cardiomyocytes has not been investigated until now. The study by Benzoni et al.¹² provides the first evidence of Strn's functional significance through a knockout model in cardiomyocytes derived from embryoid bodies. The authors observe critical dysregulation in contraction dynamics and intracellular calcium handling, alongside a higher beating rate and alterations in action potential characteristics. Their findings reveal increased densities of both transient and late sodium channel currents in the Strn knockout model. Furthermore, the authors analyze INCX activity, noting a reduction in the knockout model compared to wild-type cardiomyocytes, which suggests a potential interplay between sodium channel currents and calcium homeostasis.

Benzoni et al. propose that these observed alterations stem from a dysregulated cytoskeletal network and ion channel function due to the absence of Strn. Intriguingly, the study also explores the effects of taxol, a significant inhibitor of the late sodium current, which reverses the observed changes in the knockout model. This finding underscores the multifaceted role of Strn in not only mediating functional changes in heart muscle but also modulating broader aspects of cellular physiology.

Previous studies have indicated that cardiac Strn interacts with caveolin-3 and calmodulin in a calcium-sensitive manner, which regulates the spontaneous contraction¹³ rate of cardiomyocytes (Figure 1). Additionally, genome-wide association studies have linked the localization of Strn to changes in QRS duration, suggesting its potential involvement in heart rhythm disorders and sudden cardiac death.¹⁴ However, comprehensive studies involving larger patient cohorts are necessary to fully elucidate the role of Strn in these pathologies.

Overall, the findings presented by Benzoni et al. offer the first mechanistic evidence that the absence of Strn significantly alters both the electrical and mechanical properties of cardiomyocytes. To further understand the implications of Strn in clinical settings, large cohort studies of patients with cardiomyopathies are essential. By leveraging bioinformatics, human genetic data, and animal or in vitro models, a predictive model for Strn's role in cardiovascular disease could be developed. These insights could pave the way for establishing novel therapeutic targets for affected patients. Future research should also explore the specific signaling pathways that Strn influences within cardiomyocytes, particularly focusing on its interactions with other proteins involved in calcium signaling and contractile function. Investigating the relationship between Strn and other known modulators of cardiac function could provide a more comprehensive understanding of its role in cardiovascular health and disease. Furthermore, the potential for Strn to serve as a biomarker for cardiovascular diseases should be examined, as its expression levels may correlate with disease severity or patient outcomes. Identifying such biomarkers could facilitate early diagnosis and personalized treatment strategies for patients suffering from heart diseases.

In hypertrophic cardiomyopathy, for instance, mavacamten, a myosin inhibitor, is currently the only drug shown to decrease pressure in the left ventricular outflow tract. However, there remains a significant need for additional therapeutic options.

Exploring the role of each protein domain of Strn in preclinical settings could yield critical evidence for developing innovative treatment strategies. Various approaches should be employed to delineate the specific role of each domain, identifying which domain exerts the most significant influence on Strn's overall function. This knowledge could be pivotal in devising targeted therapies that address the underlying mechanisms of cardiovascular diseases, ultimately improving patient outcomes.

Ibrahim El-Battrawy: Writing – original draft. Nazha Hamdani: Writing – review and editing. Ibrahim Akin: Writing – review and editing.

The research was funded by EU’s Horizon 2020 research and innovation program under grant agreement No. 739593 to N.H.; DFG (Deutsche Forschungsgemeinschaft) HA 7512/2-4 and HA 7512/2-1 to N.H.; a grant from the Innovation Forum program of the Medical Faculty, RUB to I. EL-B. and N.H No. IF-023-22 and No. IF-034-22; and the Hector-Stiftung (No.; MED1814, M2401) to N.H, I. EL-B, and I.A and the German Heart foundation (F/17/23) to I. El-B. and funding from Else-Kröner-Fresenius foundation to I. El-B.