Soluble guanylyl cyclase expression is reduced in allergic asthma.
Soluble guanylyl cyclase (sGC) is an enzyme highly expressed in the lung that generates cGMP contributing to airway smooth muscle relaxation. To determine whether the bronchoconstriction observed in asthma is accompanied by changes in sGC expression, we used a well-established murine model of allergic asthma. Histological and biochemical analyses confirmed the presence of inflammation in the lungs of mice sensitized and challenged with ovalbumin (OVA). Moreover, mice sensitized and challenged with OVA exhibited airway hyperreactivity to methacholine inhalation. Steady-state mRNA levels for all sGC subunits (alpha1, alpha2, and beta1) were reduced in the lungs of mice with allergic asthma by 60-80%, as estimated by real-time PCR. These changes in mRNA were paralleled by changes at the protein level: alpha1, alpha2, and beta1 expression was reduced by 50-80% as determined by Western blotting. Reduced alpha1 and beta1 expression in bronchial smooth muscle cells was demonstrated by immunohistochemistry. To study if sGC inhibition mimics the airway hyperreactivity seen in asthma, we treated naïve mice with a selective sGC inhibitor. Indeed, in mice receiving ODQ the methacholine dose response was shifted to the left. We conclude that sGC expression is reduced in experimental asthma contributing to the observed airway hyperreactivity.
Papapetropoulos
Andreas
A
G. P. Livanos and M. Simou Laboratories, Evangelismos Hospital, Department of Critical Care and Pulmonary Services, University f Athens School of Medicine, Athens, Greece. apapapet@upatras.gr
Simoes
Davina C M
DC
Xanthou
Georgia
G
Roussos
Charis
C
Gratziou
Christina
C
D000818:Animals; D001249:Asthma / Q000201:enzymology* / Q000209:etiology*; D016535:Bronchial Hyperreactivity / Q000209:etiology / Q000503:physiopathology; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase; D006706:Homeostasis; D006967:Hypersensitivity / Q000150:complications* / Q000276:immunology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D010047:Ovalbumin / Q000276:immunology; D010069:Oxadiazoles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D016085:Bronchoconstrictor Agents; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D010069:Oxadiazoles; D011810:Quinoxalines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D016210:Methacholine Chloride; D010047:Ovalbumin; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase