Background: 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.
Methods And Results: 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)).
Conclusion: 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.
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