Department of Cardiology, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Universiteitssingel 50, 6200 MD Maastricht, The Netherlands.
Department of Molecular Genetics, Faculty of Sciences and Engineering, Maastricht University, Universiteitssingel 50, 6200 MD Maastricht, The Netherlands.
Cardiovasc Res. 2022 Sep 20;118(12):2688-2702. doi: 10.1093/cvr/cvab299.
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).
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.
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.
尽管右心室（RV）衰竭相关的死亡率和发病率很高，但与左心室（LV）相比，对其病理生理学的研究一直滞后。我们实验室的先前工作表明，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）在成年心脏中重新表达，并激活“胎儿基因程序”，在 LV 压力超负荷的情况下导致病理性心脏重塑。因此，心脏表达 Hand2 的消融可保护心脏应激，并消除在表达水平增加时观察到的适应性不良效应。在这项研究中，我们旨在了解 Hand2 对肺动脉结扎（PAB）引起的 RV 重塑的贡献。
在这项研究中，Hand2F/F 和 MCM-Hand2F/F 小鼠分别用他莫昔芬（对照组和敲除组）处理，并接受 6 周的 RV 压力超负荷诱导的 PAB。对所有实验组进行超声心动图和 MRI 衍生的血流动力学参数以及分子重塑评估，并与假手术对照组进行比较。PAB 后 6 周，对照组动物的 Hand2 表达水平升高，但如预期的那样，敲除组心脏中仍不存在。尽管 Hand2 表达存在明显差异，但压力超负荷导致心脏功能受损，与基因型无关。事实上，Hand2 耗竭似乎使 RV 对压力超负荷更加敏感，因为这些小鼠发生更多的肥大和更严重的心脏功能障碍。在患有肺动脉高压的人类心脏的 RV 样本中也观察到更高水平的 HAND2 表达。反过来，RV 压力超负荷心脏的 LV 也受到明显影响，表现为形状改变、LV 质量减少和心脏功能受损。RNA 测序显示，与以前描述的 LV 压力超负荷相比，在压力超负荷的 RV 中有一组独特的基因失调。
心脏特异性 Hand2 耗竭与 RV 压力超负荷时严重的心脏功能障碍相关。虽然抑制 Hand2 表达可以预防 LV 压力超负荷时的心脏功能障碍，但对 RV 压力超负荷时却不起作用。这项研究强调需要更好地了解驱动 RV 病理性重塑的分子机制，与 LV 相反，以便更好地诊断和治疗 RV 或 LV 衰竭的患者。
