Signalisation et Physiopathologie Cardiovasculaire, UMR-S 1180, Univ. Paris-Sud, INSERM, Université Paris-Saclay, Châtenay-Malabry 92296, France.
Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre, France; Assistance Publique Hôpitaux de Paris, Service de Pneumologie, Hôpital Bicêtre, Le Kremlin Bicêtre, France; Inserm UMR_S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France.
J Mol Cell Cardiol. 2018 May;118:208-224. doi: 10.1016/j.yjmcc.2018.04.003. Epub 2018 Apr 7.
Right ventricular (RV) function is the most important prognostic factor for pulmonary arterial hypertension (PAH) patients. The progressive increase of pulmonary vascular resistance induces RV hypertrophy (RVH) and at term RV failure (RVF). However, the molecular mechanisms of RVH and RVF remain understudied. In this study, we gained insights into cytosolic Ca signaling remodeling in ventricular cardiomyocytes during the pathogenesis of severe pulmonary hypertension (PH) induced in rats by monocrotaline (MCT) exposure, and we further identified molecular candidates responsible for this Ca remodeling.
After PH induction, hypertrophied RV myocytes presented longer action potential duration, higher and faster [Ca] transients and increased sarcoplasmic reticulum (SR) Ca content, whereas no changes in these parameters were detected in left ventricular (LV) myocytes. These modifications were associated with increased P-Ser-phospholamban pentamer expression without altering SERCA2a (Sarco/Endoplasmic Reticulum Ca-ATPase) pump abundance. Moreover, after PH induction, Ca sparks frequency were higher in hypertrophied RV cells, while total RyR2 (Ryanodine Receptor) expression and phosphorylation were unaffected. Together with cellular hypertrophy, the T-tubules network was disorganized. Hypertrophied RV cardiomyocytes from MCT-exposed rats showed decreased expression of classical STIM1 (Stromal Interaction molecule) associated with increased expression of muscle-specific STIM1 Long isoform, glycosylated-Orai1 channel form, and TRPC1 and TRPC4 channels, which was correlated with an enhanced Ca-release-activated Ca (CRAC)-like current. Pharmacological inhibition of TRPCs/Orai1 channels in hypertrophied RV cardiomyocytes normalized [Ca] transients amplitude, the SR Ca content and cell contractility to control levels. Finally, we showed that most of these changes did not appear in LV cardiomyocytes.
These new findings demonstrate RV-specific cellular Ca cycling remodeling in PH rats with maladaptive RVH and that the STIM1L/Orai1/TRPC1/C4-dependent Ca current participates in this Ca remodeling in RVH secondary to PH.
右心室（RV）功能是肺动脉高压（PAH）患者最重要的预后因素。肺血管阻力的逐渐增加导致 RV 肥厚（RVH）和终末期 RV 衰竭（RVF）。然而，RVH 和 RVF 的分子机制仍研究不足。在这项研究中，我们深入了解了野百合碱（MCT）暴露诱导的大鼠严重肺动脉高压（PH）发病过程中心室肌细胞细胞溶质 Ca 信号转导重构，并进一步确定了导致这种 Ca 重构的分子候选物。
PH 诱导后，肥大的 RV 心肌细胞呈现更长的动作电位持续时间、更高和更快的 [Ca] 瞬变以及增加的肌浆网（SR）Ca 含量，而左心室（LV）心肌细胞中没有检测到这些参数的变化。这些变化与 P-Ser-磷调蛋白五聚体表达增加有关，而不改变 SERCA2a（肌浆网/内质网 Ca-ATP 酶）泵的丰度。此外，PH 诱导后，肥大的 RV 细胞中的 Ca 火花频率更高，而总 RyR2（Ryanodine Receptor）表达和磷酸化不受影响。与细胞肥大一起，T 小管网络变得紊乱。MCT 暴露大鼠的肥大 RV 心肌细胞显示经典 STIM1（基质相互作用分子）表达降低，与肌肉特异性 STIM1 Long 异构体、糖基化 Orai1 通道形式以及 TRPC1 和 TRPC4 通道表达增加有关，这与增强的 Ca 释放激活的 Ca（CRAC）样电流有关。在肥大的 RV 心肌细胞中，药理学抑制 TRPCs/Orai1 通道可使 [Ca] 瞬变幅度、SR Ca 含量和细胞收缩力恢复正常。最后，我们表明这些变化中的大多数在 LV 心肌细胞中并未出现。
这些新发现表明 PH 大鼠 RV 特异性细胞 Ca 循环重构与适应性 RVH 有关，并且 STIM1L/Orai1/TRPC1/C4 依赖性 Ca 电流参与了 PH 继发 RVH 中的这种 Ca 重构。
