Egom Emmanuel Eroume-A, Feridooni Tiam, Pharithi Rebabonye B, Khan Barkat, Shiwani Haaris A, Maher Vincent, El Hiani Yassine, Rose Robert A, Pasumarthi Kishore Bs, Ribama Hilaire A
Egom Clinical & Translational Research Services Ltd.,Dartmouth, NS B3H 3H3, Canada.
Department of Cardiology, The Adelaide and Meath HospitalTallaght, Dublin, Ireland.
Int J Physiol Pathophysiol Pharmacol. 2017 Sep 1;9(4):112-118. eCollection 2017.
Pulmonary Arterial Hypertension (PAH) is a deadly and disabling disease for which there is no marketed drug that addresses the underlying disease mechanism and targets to cure patients. The lack of understanding of the disease mechanism represents the main challenges in developing curative therapies. We here report, for the first time, that mice lacking natriuretic peptides clearance receptor develop PAH.
Initial studies assessed cardiac structure and function in NPR-C (wild type) and age matched, littermate NPR-C mice by echocardiography. Mice lacking NPR-C had right atrial dilation, tricuspid regurgitation as well as echocardiographic signs of right ventricular pressure overload, including flattening and paradoxical bulging of the septum into the left ventricle during systole, and hypertrophy of the right ventricular free wall. Among the 10 NPR-C mice aged between 12 and 20 weeks studied, 8 showed the above typical echocardiographic features of PAH [80%, 95% CI: (0.4439-0.9748)], and only one had pericardial effusion [10%, 95% CI: (0.0025-0.4450)], finding that has a prognostic significance in subjects affected by this clinical entity. To confirm the presence of increased right ventricular systolic pressure (RVSP) among NPR-C mice, right heart catheterization was performed. Strikingly, RVSP was significantly elevated in NPR-C mice compared to their age matched, littermate NPR-C mice, at baseline (21.95±0.56 mmHg vs. 5.3±0.6 mmHg, respectively (P<0.001)).
The above results suggest that NPR-C-mediated signalling pathways play a critical role in the development of PAH, indicating that NPR-C is an important protective receptor in the heart rather than just being a clearance receptor.
肺动脉高压（PAH）是一种致命且使人丧失活动能力的疾病，目前尚无针对潜在疾病机制并旨在治愈患者的上市药物。对疾病机制缺乏了解是开发治愈性疗法的主要挑战。我们在此首次报告，缺乏利钠肽清除受体的小鼠会发生PAH。
最初的研究通过超声心动图评估了NPR-C（野生型）和年龄匹配的同窝NPR-C基因敲除小鼠的心脏结构和功能。缺乏NPR-C的小鼠出现右心房扩张、三尖瓣反流以及右心室压力过载的超声心动图表现，包括收缩期室间隔变平并向左侧心室矛盾性膨出，以及右心室游离壁肥厚。在研究的10只年龄在12至20周之间的NPR-C基因敲除小鼠中，8只表现出上述PAH的典型超声心动图特征[80%，95%可信区间：（0.4439 - 0.9748）]，只有1只出现心包积液[10%，95%可信区间：（0.0025 - 0.4450）]，这一发现对受该临床病症影响的患者具有预后意义。为了确认NPR-C基因敲除小鼠中右心室收缩压（RVSP）升高，进行了右心导管检查。令人惊讶的是，与年龄匹配的同窝NPR-C小鼠相比，NPR-C基因敲除小鼠在基线时RVSP显著升高（分别为21.95±0.56 mmHg和5.3±0.6 mmHg，P<0.001）。
上述结果表明，NPR-C介导的信号通路在PAH的发生发展中起关键作用，这表明NPR-C不仅是一个清除受体，还是心脏中的重要保护受体。
