The Role of Soluble Guanylyl Cyclase in Chronic Obstructive Pulmonary Disease

• Published in: American journal of respiratory and critical care medicine Vol. 188; no. 7; pp. 789 - 799
• Main Authors: Glynos, Constantinos, Dupont, Lisa L., Vassilakopoulos, Theodoros, Papapetropoulos, Andreas, Brouckaert, Peter, Giannis, Athanassios, Joos, Guy F., Bracke, Ken R., Brusselle, Guy G.
• Format: Journal Article
• Language: English
• Published: New York, NY American Thoracic Society 01.10.2013
• Subjects: Aged; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Asthma; Biological and medical sciences; Bronchoconstriction - drug effects; Bronchoconstriction - physiology; Chronic obstructive pulmonary disease; Chronic obstructive pulmonary disease, asthma; Cigarettes; Disease Models, Animal; Down-Regulation; Enzymes; Female; Guanylate Cyclase - analysis; Guanylate Cyclase - deficiency; Guanylate Cyclase - physiology; Human subjects; Humans; Inflammation; Intensive care medicine; Kinases; Lavage; Male; Medical sciences; Mice; Mice, Inbred C57BL; Middle Aged; Nitric oxide; Pneumology; Polymerase chain reaction; Proteins; Pulmonary Disease, Chronic Obstructive - physiopathology; Receptors, Cytoplasmic and Nuclear - analysis; Receptors, Cytoplasmic and Nuclear - deficiency; Receptors, Cytoplasmic and Nuclear - physiology; Respiratory Mucosa - chemistry; Serotonin; Serotonin - physiology; Smoking - adverse effects; Smoking - physiopathology; Smooth muscle; Soluble Guanylyl Cyclase; Tobacco Smoke Pollution - adverse effects; Tobacco, tobacco smoking; Toxicology; Lung disease; Intensive care; Enzyme; Respiratory disease; Tobacco smoking; Phosphorus-oxygen lyases; Lyases; Soluble form; Guanylate cyclase; cigarette smoking; soluble guanylyl cyclase; Bronchus disease; Chronic obstructive pulmonary disease; Resuscitation
• ISSN: 1073-449X; 1535-4970; 1535-4970
• DOI: 10.1164/rccm.201210-1884OC

Soluble guanylyl cyclase (sGC), a cyclic guanosine 5'-monophosphate-generating enzyme, regulates smooth muscle tone and exerts antiinflammatory effects in animal models of asthma and acute lung injury. In chronic obstructive pulmonary disease (COPD), primarily caused by cigarette smoke (CS), lung inflammation persists and smooth muscle tone remains elevated, despite ample amounts of nitric oxide that could activate sGC. To determine the expression and function of sGC in patients with COPD and in a murine model of COPD. Expression of sGCα1, α2, and β1 subunits was examined in lungs of never-smokers, smokers without airflow limitation, and patients with COPD; and in C57BL/6 mice after 3 days, 4 weeks, and 24 weeks of CS exposure. The functional role of sGC was investigated in vivo by measuring bronchial responsiveness to serotonin in mice using genetic and pharmacologic approaches. Pulmonary expression of sGC, both at mRNA and protein level, was decreased in smokers without airflow limitation and in patients with COPD, and correlated with disease severity (FEV1%). In mice, exposure to CS reduced sGC, cyclic guanosine 5'-monophosphate levels, and protein kinase G activity. sGCα1(-/-) mice exposed to CS exhibited bronchial hyperresponsiveness to serotonin. Activation of sGC by BAY 58-2667 restored the sGC signaling and attenuated bronchial hyperresponsiveness in CS-exposed mice. Down-regulation of sGC because of CS exposure might contribute to airflow limitation in COPD.