Antigny Fabrice, Luo Rui, Perrier Romain, Masson Bastien, Fadel Guillaume, Ruffenach Grégoire, Saint-Martin Willer Anaïs, Akamkam Ali, Grynblat Julien, Jaïs Xavier, Le Pavec Jerôme, Dang Van Simon, Brunet Dorothée, Lefebvre Florence, Gérard Garance, Domenichini Séverine, Boët Angèle, Guihaire Julien, Gomez Ana-Maria, Montani David, Benitah Jean-Pierre, Humbert Marc, Mercier Olaf, Sabourin Jessica
Université Paris-Saclay, Inserm, UMR-S 999, Hypertension Pulmonaire: Physiopathologie and Innovation Thérapeutique (HPPIT), AP-HP, Hôpital Bicêtre, Hôpital Marie Lannelongue (Groupe Hospitalier Paris Saint Joseph), ERN-LUNG, Le Plessis Robinson, France (F.A., B.M., G.F., G.R., A.S.-M.W., A.A., J. Grynblat, X.J., J.L.P., S.D.V., D.B., A.B., J. Guihaire, D.M., M.H., O.M.).
Inserm, UMR-S 1180, Signalisation et Physiopathologie Cardiovasculaire, Université Paris-Saclay, Orsay, France (R.L., R.P., F.L., G.G., A.-M.G., J.-P.B., J.S.).
Circ Heart Fail. 2025 May;18(5):e012293. doi: 10.1161/CIRCHEARTFAILURE.124.012293. Epub 2025 Apr 18.
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 Ca 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.
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.
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 Ca signaling. At the cellular level, CTEPH myocytes presented reduced L-type Ca current in association with reduced mRNA of . Furthermore, CTEPH myocytes showed lower [Ca] transients, decreased sarcoplasmic reticulum Ca content, and decreased cell shortening, related to reduced SERCA2a (Sarco/endoplasmic reticulum Ca-ATPase isoform 2a) protein expression. Moreover, CTEPH cardiomyocytes exhibited reduced Ca spark occurrence, which relied on smaller RyR2 (ryanodine receptor 2) clusters and T-tubule disorganization. Finally, these alterations in Ca homeostasis were also associated with an increased store-operated Ca entry and the de novo expression of the Ca sensor protein STIM1L (stromal interaction molecule 1 long isoform) in CTEPH myocytes as well as in RV from human patients with pulmonary arterial hypertension.
Our data reveal cellular Ca cycling remodeling that participates in the pathogenesis of RV dysfunction and may constitute therapeutic targets to limit the development of RV dysfunction.
肺动脉高压是一种因右心室（RV）衰竭导致死亡率很高的严重疾病。由于缺乏相关动物模型，参与RV重塑（包括钙处理）的分子和细胞过程仍不清楚。在本研究中，我们旨在更好地了解RV衰竭所涉及的病理生理机制。
我们使用慢性血栓栓塞性肺动脉高压（CTEPH）猪模型，该模型会导致渐进性RV肥大和功能障碍。对CTEPH猪和假手术猪的RV心肌细胞进行了细胞、分子无偏倚的全转录组分析和生化分析。
CTEPH猪复制了人类CTEPH特征的血流动力学和组织学变化。对假手术猪和CTEPH猪的转录组分析揭示了与失代偿性RV功能的肺动脉高压人类患者相似的分子RV重塑，并特别确定了参与钙信号传导的基因变化。在细胞水平上，CTEPH心肌细胞的L型钙电流减少，同时相关mRNA也减少。此外，CTEPH心肌细胞表现出较低的[Ca]瞬变、肌浆网钙含量降低和细胞缩短减少，这与SERCA2a（肌浆网/内质网钙-ATP酶同工型2a）蛋白表达降低有关。此外，CTEPH心肌细胞的钙火花发生率降低，这依赖于较小的RyR2（雷诺丁受体2）簇和T管紊乱。最后，这些钙稳态的改变还与CTEPH心肌细胞以及肺动脉高压人类患者RV中储存操纵性钙内流增加和钙传感器蛋白STIM1L（基质相互作用分子1长同工型）的从头表达有关。
我们的数据揭示了参与RV功能障碍发病机制的细胞钙循环重塑，这可能构成限制RV功能障碍发展的治疗靶点。
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