Pulmonary Arterial Hypertension Due to NPR-C Mutation: A Novel Paradigm for Normal and Pathologic Remodeling?

Abstract

Idiopathic Pulmonary Arterial Hypertension (IPAH) is a deadly and disabling disease characterized by severe vascular remodeling of small pulmonary vessels by fibroblasts, myofibroblasts and vascular smooth muscle cell proliferation. Recent studies suggest that the Natriuretic Peptide Clearance Receptor (NPR-C) signaling pathways may play a crucial role in the development of IPAH. Reduced expression or function of NPR-C signaling in pulmonary artery smooth muscle cells may contribute to the pulmonary vascular remodeling, which is characteristic of this disease. The likely mechanisms may involve an impaired interaction between NPR-C, specific growth factors and other signal transduction pathways including but not limited to Gqα/mitogen-activated protein kinase (MAPK)/PI3K and AKT signaling. The resulting failure of growth suppression in pulmonary artery smooth muscle cells provides critical clues to the cellular pathobiology of IPAH. The reciprocal regulation of NPR-C signaling in models of tissue remodeling may thus provide new insights to our understanding of IPAH.

Natriuretic Peptides in the Cardiovascular System: Multifaceted Roles in Physiology, Pathology and Therapeutics

“…Among the recent discoveries regarding the NPs system, the one that deserves particular attention is the potential involvement of NPRC signaling in the pathogenesis of pulmonary arterial hypertension [46]. The article by Egom E. provides a revision of the literature supporting the link between abnormalities of NPRC signaling and pulmonary vascular remodeling, pulmonary fibrosis, and chronic obstructive pulmonary disease [47]. The latter are explained by the disruption of the anti-proliferative effects of NPRC via the Gqα/mitogen-activated protein (MAP) kinase signaling pathway [48].…”

Novel Insights Regarding Nitric Oxide and Cardiovascular Diseases

“…The pathogenesis of the different types of pulmonary hypertension (PH), and in particular of pulmonary arterial hypertension (PAH), is not completely known, but several studies suggested an alteration of vasoconstriction/vasodilation and proliferation/antiproliferation as possible pathogenic mechanisms. 85 The bioavailability of NO and signaling pathway is impaired in experimental models and in patients with PH. 86…”

Role of natriuretic peptide receptor C signalling in obesity‐induced heart failure with preserved ejection fraction with pulmonary hypertension

“…4,5,7 In addition, mice lacking NPRC exhibit right atrial dilation, hypertrophy of the RV free wall and trabeculae, tricuspid regurgitation as well as echocardiographic findings suggestive of RV pressure overload, including flattening and paradoxical bulging of the septum into the left ventricle during systole, which are all findings typically seen in humans with PAH. 4,5,8,9 Consistently, Doppler echocardiography assessment revealed a significantly higher RV systolic pressure compared with wild-type littermates. 4,5,8,9 These findings were also confirmed by resting right heart catheterization.…”

“…Miller and colleagues have elegantly showed that the development of PH in HFpEF may largely be determined by the presence and the severity of diastolic dysfunction, 2 which in turn has been shown to predict functional capacity and clinical worsening in PH. 3–5 Interestingly, alterations in NPRC signalling have been independently associated with the development of diastolic dysfunction in a random large cohort of people from Olmsted County (Minnesota, USA), suggesting the potential and crucial beneficial role of NPR-C signal transduction in the pathophysiology of PH-HFpEF. 6 Most importantly, the authors demonstrated that the development of diastolic dysfunction was independent of age, sex, BMI and arterial hypertension in the homozygotes for this NPR3 genotype with an odds ratio of 1.9 similar to that of arterial hypertension, a major risk factor for diastolic dysfunction.…”

“…6 Most importantly, the authors demonstrated that the development of diastolic dysfunction was independent of age, sex, BMI and arterial hypertension in the homozygotes for this NPR3 genotype with an odds ratio of 1.9 similar to that of arterial hypertension, a major risk factor for diastolic dysfunction. 4–6…”