title: Effect of nitric oxide deficiency on the pulmonary PTHrP system.
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 (PTHrP) expression is a key regulator of pulmonary fibrosis and development, the effect of chronic NO deficiency on the pulmonary PTHrP 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 PTHrP, 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 NOX2, p47phox and p67phox. Furthermore, L-NAME induced the pulmonary expression of PTHrP and of its corresponding receptor, PTH-1R. Expression of PTHrP and PTH-1R correlated with the expression of two well-established PTHrP downstream targets, ADRP and PPARγ, suggesting an activation of the pulmonary PTHrP system by NO deficiency. Captopril reduced the expression of PTHrP, profibrotic markers and ornithine decarboxylase, but neither that of PTH-1R nor that of ADRP and PPARγ. All transcriptional changes were confirmed in NOS-3-deficient mice. In conclusion, NOS-3-derived NO suppresses pulmonary PTHrP and PTH-1R expression, thereby modifying pulmonary remodelling.
authors: Physiologisches Institut, Justus-Liebig-Universität Gießen, Gießen, Germany.
authors: Bastian
authors: B
authors: Brockhoff
authors: Physiologisches Institut, Justus-Liebig-Universität Gießen, Gießen, Germany.
authors: Rolf
authors: R
authors: Schreckenberg
authors: Physiologisches Institut, Justus-Liebig-Universität Gießen, Gießen, Germany.
authors: Svenja
authors: S
authors: Forst
authors: Physiologisches Institut, Justus-Liebig-Universität Gießen, Gießen, Germany.
authors: Jacqueline
authors: J
authors: Heger
authors: Pharmahungary Group, Szeged, Hungary.|Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged, Hungary.
authors: Péter
authors: P
authors: Bencsik
authors: Pharmahungary Group, Szeged, Hungary.|Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged, Hungary.
authors: Krisztina
authors: K
authors: Kiss
authors: Pharmahungary Group, Szeged, Hungary.|Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.
authors: Peter
authors: P
authors: Ferdinandy
authors: Physiologisches Institut, Justus-Liebig-Universität Gießen, Gießen, Germany.
authors: Rainer
authors: R
authors: Schulz
authors: Physiologisches Institut, Justus-Liebig-Universität Gießen, Gießen, Germany.
authors: Klaus-Dieter
authors: KD
authors: Schlüter
mesh_terms: D000818:Animals; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008171:Lung Diseases / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000172:deficiency*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism*; D051381:Rats; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology
chemical_list: D009573:Nitrites; D044162:Parathyroid Hormone-Related Protein; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester
keywords: 
  ADRP
  ; PPARγ; elastin; lung fibrosis