Department of Physiology, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland, 1023, New Zealand.
School of Biological Sciences, University of Auckland, Private Bag 92019, Auckland, 1023, New Zealand.
Pflugers Arch. 2018 Jul;470(7):1115-1126. doi: 10.1007/s00424-018-2125-0. Epub 2018 Mar 10.
Currently, there are no tailored therapies available for the treatment of right ventricular (RV) hypertrophy, and the cellular mechanisms that underlie the disease are poorly understood. We investigated the cellular changes that occur early in the progression of the disease, when RV hypertrophy is evident, but prior to the onset of heart failure. Intracellular Ca ([Ca]) handling was examined in a rat model of monocrotaline (MCT)-induced pulmonary hypertension and subsequent RV hypertrophy. [Ca] and stress production were measured in isolated RV trabeculae under baseline conditions (1-Hz stimulation, 1.5 mM [Ca], 37 °C), and in response to inotropic interventions (5-Hz stimulation or 1-μM isoproterenol). Under baseline conditions, MCT trabeculae had impaired Ca release in response to stimulation with a 45% delay in the time-to-peak Ca, but there was no difference in the amplitude and decay of the Ca transient, or active stress relative to RV trabeculae from normotensive hearts (CON). Increasing stimulation frequency from 1 to 5 Hz increased stress in CON, but not MCT trabeculae. Similarly, β-adrenergic stimulation with isoproterenol increased Ca transient amplitude and active stress in CON, but not in MCT trabeculae, despite accelerating Ca transient decay in trabeculae from both groups. During isoproterenol treatment, MCT trabeculae showed increased diastolic Ca leak, which may explain the blunted inotropic response to β-adrenergic stimulation. Confocal imaging of trabeculae fixed following functional measurements showed that myocytes were on average wider, and transverse-tubule organisation was disrupted in MCT which provides a mechanism to explain the observed slower release of Ca.
目前，尚无针对右心室（RV）肥大治疗的定制疗法，并且该病的细胞机制尚不清楚。我们研究了疾病早期进展时发生的细胞变化，此时 RV 肥大明显，但尚未发生心力衰竭。我们在野百合碱（MCT）诱导的肺动脉高压和随后的 RV 肥大的大鼠模型中研究了细胞内 Ca（[Ca]）处理。在基线条件下（1-Hz 刺激，1.5mM[Ca]，37°C）以及对变力干预（5-Hz 刺激或 1-μM 异丙肾上腺素）的反应下，测量了分离的 RV 小梁中的[Ca]和应激产生。在基线条件下，MCT 小梁对刺激的 Ca 释放有障碍，峰值 Ca 的时间延迟了 45%，但 Ca 瞬变的幅度和衰减以及与正常血压心脏（CON）的 RV 小梁相比，主动应激没有差异。将刺激频率从 1 增加到 5 Hz 会增加 CON 的应激，但不会增加 MCT 小梁的应激。同样，β-肾上腺素能刺激异丙肾上腺素增加 CON 的 Ca 瞬变幅度和主动应激，但不会增加 MCT 小梁的 Ca 瞬变幅度和主动应激，尽管两组小梁中的 Ca 瞬变衰减都加快了。在异丙肾上腺素治疗期间，MCT 小梁显示出舒张 Ca 渗漏增加，这可能解释了对β-肾上腺素能刺激的变力反应迟钝。在功能测量后固定小梁的共聚焦成像显示，与 CON 相比，MCT 中的心肌细胞平均更宽，横管组织紊乱，这提供了一种解释观察到的 Ca 释放更慢的机制。
