Aims Research on the pathophysiology of right ventricular (RV) failure has, in spite of the associated high mortality and morbidity, lagged behind compared to the left ventricle (LV). Previous work from our lab revealed that the embryonic basic helix-loop-helix transcription factor heart and neural crest derivatives expressed-2 (Hand2) is re-expressed in the adult heart and activates a ‘foetal gene programme’ contributing to pathological cardiac remodelling under conditions of LV pressure overload. As such, ablation of cardiac expression of Hand2 conferred protection to cardiac stress and abrogated the maladaptive effects that were observed upon increased expression levels. In this study, we aimed to understand the contribution of Hand2 to RV remodelling in response to pressure overload induced by pulmonary artery banding (PAB). Methods and results In this study, Hand2F/F and MCM- Hand2F/F mice were treated with tamoxifen (control and knockout, respectively) and subjected to six weeks of RV pressure overload induced by PAB. Echocardiographic- and MRI-derived haemodynamic parameters as well as molecular remodelling were assessed for all experimental groups and compared to sham-operated controls. Six weeks after PAB, levels of Hand2 expression increased in the control-banded animals but, as expected, remained absent in the knockout hearts. Despite the dramatic differences in Hand2 expression, pressure overload resulted in impaired cardiac function independently of the genotype. In fact, Hand2 depletion seems to sensitize the RV to pressure overload as these mice develop more hypertrophy and more severe cardiac dysfunction. Higher expression levels of HAND2 were also observed in RV samples of human hearts from patients with pulmonary hypertension. In turn, the LV of RV pressure-overloaded hearts was also dramatically affected as reflected by changes in shape, decreased LV mass, and impaired cardiac function. RNA-sequencing revealed a distinct set of genes that are dysregulated in the pressure-overloaded RV, compared to the previously described pressure-overloaded LV. Conclusion Cardiac-specific depletion of Hand2 is associated with severe cardiac dysfunction in conditions of RV pressure overload. While inhibiting Hand2 expression can prevent cardiac dysfunction in conditions of LV pressure overload, the same does not hold true for conditions of RV pressu re overload. This study highlights the need to better understand the molecular mechanisms driving pathological remodelling of the RV in contrast to the LV, in order to better diagnose and treat patients with RV or LV failure.

中文翻译：

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成人心脏需要转录因子 Hand2 的基线表达以承受右心室压力超负荷

目标 与左心室 (LV) 相比，尽管相关的高死亡率和发病率，但对右心室 (RV) 衰竭的病理生理学的研究仍然落后。我们实验室以前的工作表明，胚胎基本螺旋-环-螺旋转录因子心脏和神经嵴衍生物表达-2（Hand2）在成人心脏中重新表达并激活“胎儿基因程序”，有助于病理性心脏重塑LV 压力过载的条件。因此，Hand2 心脏表达的消融赋予了对心脏压力的保护作用，并消除了在表达水平增加时观察到的适应不良效应。在这项研究中，我们旨在了解 Hand2 对 RV 重塑的贡献，以响应肺动脉束带 (PAB) 引起的压力过载。方法和结果 在这项研究中，Hand2F/F 和 MCM-Hand2F/F 小鼠分别用他莫昔芬（对照和敲除）治疗，并经受 PAB 诱导的 RV 压力超负荷六周。评估所有实验组的超声心动图和 MRI 衍生的血流动力学参数以及分子重塑，并与假手术对照组进行比较。PAB 后六周，Hand2 表达水平在对照带状动物中增加，但正如预期的那样，在敲除心脏中仍然不存在。尽管 Hand2 表达存在显着差异，但压力超负荷导致心脏功能受损，与基因型无关。事实上，Hand2 耗竭似乎会使 RV 对压力过载敏感，因为这些小鼠会出现更多的肥大和更严重的心脏功能障碍。在来自肺动脉高压患者的人类心脏的 RV 样本中也观察到 HAND2 的较高表达水平。反过来，RV 压力超负荷心脏的 LV 也受到显着影响，表现为形状变化、LV 质量减少和心脏功能受损。与之前描述的压力超载 LV 相比，RNA 测序揭示了一组不同的基因，这些基因在压力超载 RV 中失调。结论 心脏特异性 Hand2 耗竭与 RV 压力超负荷条件下的严重心功能不全相关。虽然抑制 Hand2 表达可以预防 LV 压力超负荷条件下的心功能不全，但同样不适用于 RV 压力超负荷条件。