SND1 Impairs Calcium Homeostasis in Right Ventricular Failure by Binding and Destabilizing SERCA2a in Cardiomyocytes
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Background
Right ventricular failure (RVF) is a major contributor to a poor prognosis in patients with pulmonary arterial hypertension (PAH); however, its underlying molecular mechanisms remain incompletely understood. We identified a significant upregulation of the cardiac fetal gene SND1 in the right ventricular myocardium of RVF rats. This upregulation may be a key component of cardiac fetal reprogramming and play a critical role in RVF progression. However, the precise molecular mechanisms by which SND1 contributes to RVF remain unelucidated.
Methods
Rat models of PAH were established by intraperitoneal injection of monocrotaline (MCT). The pulmonary artery pressure and right ventricular function of rats were assessed using transthoracic echocardiography combined with right heart catheterization. Weighted gene co-expression network analysis (WGCNA) of proteomic data identified a significant association between SND1 upregulation and RVF progression. Calcium transient and contractility measurements in single cardiomyocytes were performed to evaluate the effect of SND1 on sarcoplasmic reticulum (SR) function. Liquid chromatography with mass spectrometry/mass spectrometry analysis combined with co-immunoprecipitation (Co-IP) was used to identify sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase 2A (SERCA2a) as the protein interacting with SND1. The effect of SND1 on the progression of RVF was validated using cardiomyocyte-specific SND1 conditional knockout rats.
Results
Proteomic and molecular analyses revealed that the cardiac fetal gene SND1 is reactivated in RVF and may contribute to disease progression. In vitro, SND1 knockdown in neonatal rat ventricular myocytes (NRVMs) enhanced contractility, improved calcium transient amplitude and velocity, and increased cell survival under calcium overload. Mechanistically, SND1 interacts with SERCA2a and promotes its proteasomal degradation, impairing SR calcium reuptake. SND1 knockdown restored SERCA2a stability. In vivo, cardiomyocyte-specific SND1 knockout improved right ventricular function, reduced SERCA2a degradation and apoptosis, and increased survival in RVF rats.
Conclusion
Our study revealed that SND1 reactivation (a fetal gene) contributes to the progression of RVF by promoting SERCA2a degradation and impairing calcium handling. Targeted suppression of SND1 enhances cardiomyocyte contractility and survival, highlighting SND1 as a potential therapeutic target for improving right ventricular function in PAH.
Clinical perspective
What Is New?
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This study identifies SND1, a reactivated fetal gene, as a key contributor to right ventricular failure (RVF) progression in pulmonary arterial hypertension (PAH).
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SND1 interacts with SERCA2a, promoting its proteasomal degradation, which disrupts sarcoplasmic reticulum calcium reuptake and weakens cardiomyocyte contractility.
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Cardiomyocyte-specific SND1 deletion restores SERCA2a levels, improves calcium handling, enhances right ventricular function, and increases survival in RVF rats.
What Are the Clinical Implications?
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The reactivation of fetal genes such as SND1 is not just a marker but a pathogenic driver in maladaptive right ventricular remodeling.
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Targeting SND1 represents a novel therapeutic approach to improve right ventricular contractility and prevent heart failure progression in patients with PAH.
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These findings may inform the development of gene- or protein-targeted therapies aimed at stabilizing SERCA2a and preserving right heart function in high-risk populations.
