Open AccessEffect of nitric oxide deficiency on the pulmonary PTH rP system
Author(s) -
Brockhoff Bastian,
Schreckenberg Rolf,
Forst Svenja,
Heger Jacqueline,
Bencsik Péter,
Kiss Krisztina,
Ferdinandy Peter,
Schulz Rainer,
Schlüter KlausDieter
Publication year - 2017
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12942
Subject(s) - medicine , endocrinology , pulmonary hypertension , parathyroid hormone , pulmonary fibrosis , nitric oxide , chemistry , oxidative stress , lung , calcium
Abstract Nitric oxide ( NO ) deficiency is common in pulmonary diseases, but its effect on pulmonary remodelling is still controversial. As pulmonary parathyroid hormone‐related protein ( PTH rP) expression is a key regulator of pulmonary fibrosis and development, the effect of chronic NO deficiency on the pulmonary PTH rP system and its relationship with oxidative stress was addressed. NO bioavailability in adult rats was reduced by systemic administration of L‐ NAME via tap water. To clarify the role of NO synthase ( NOS )‐3‐derived NO on pulmonary expression of PTH rP, NOS ‐3‐deficient mice were used. Captopril and hydralazine were used to reduce the hypertensive effect of L‐ NAME treatment and to interfere with the pulmonary renin‐angiotensin system ( RAS ). Quantitative RT ‐ PCR and immunoblot techniques were used to characterize the expression of key proteins involved in pulmonary remodelling. L‐ NAME administration significantly reduced pulmonary NO concentration and caused oxidative stress as characterized by increased pulmonary nitrite concentration and increased expression of NOX 2, p47phox and p67phox. Furthermore, L‐ NAME induced the pulmonary expression of PTH rP and of its corresponding receptor, PTH ‐1R. Expression of PTH rP and PTH ‐1R correlated with the expression of two well‐established PTH rP downstream targets, ADRP and PPAR γ, suggesting an activation of the pulmonary PTH rP system by NO deficiency. Captopril reduced the expression of PTH rP, profibrotic markers and ornithine decarboxylase, but neither that of PTH ‐1R nor that of ADRP and PPAR γ. All transcriptional changes were confirmed in NOS ‐3‐deficient mice. In conclusion, NOS ‐3‐derived NO suppresses pulmonary PTH rP and PTH ‐1R expression, thereby modifying pulmonary remodelling.