Ca2+ Cycling Alteration in a Porcine Model of Right Ventricular Dysfunction.

Background

Pulmonary hypertension is a severe disease with high mortality rates due to right ventricular (RV) failure. The molecular and cellular processes involved in RV remodeling, including Ca2+ handling, remain elusive due to the lack of relevant animal models. In this study, we aim to understand better the pathophysiological mechanisms involved in RV failure.

Methods

We used the chronic thromboembolic pulmonary hypertension (CTEPH) pig model, which leads to progressive RV hypertrophy and dysfunction. Cellular, molecular unbiased global transcriptional profiling and biochemical analyses were performed on RV cardiomyocytes from CTEPH and Sham-operated pigs.

Results

CTEPH pigs replicated the hemodynamics and histological changes of human CTEPH features. Transcriptome analysis in Sham and CTEPH pigs revealed molecular RV remodeling close to human patients with pulmonary arterial hypertension with decompensated RV function and notably identified changes in genes involved in Ca2+ signaling. At the cellular level, CTEPH myocytes presented reduced L-type Ca2+ current in association with reduced mRNA of CACNA1C. Furthermore, CTEPH myocytes showed lower [Ca2+]i transients, decreased sarcoplasmic reticulum Ca2+ content, and decreased cell shortening, related to reduced SERCA2a (Sarco/endoplasmic reticulum Ca2+-ATPase isoform 2a) protein expression. Moreover, CTEPH cardiomyocytes exhibited reduced Ca2+ spark occurrence, which relied on smaller RyR2 (ryanodine receptor 2) clusters and T-tubule disorganization. Finally, these alterations in Ca2+ homeostasis were also associated with an increased store-operated Ca2+ entry and the de novo expression of the Ca2+ sensor protein STIM1L (stromal interaction molecule 1 long isoform) in CTEPH myocytes as well as in RV from human patients with pulmonary arterial hypertension.

Conclusions

Our data reveal cellular Ca2+ cycling remodeling that participates in the pathogenesis of RV dysfunction and may constitute therapeutic targets to limit the development of RV dysfunction.