30 research outputs found
Gender-Specific Modulation of the Response to Arterial Injury by Soluble Guanylate Cyclase α1
Objective: Soluble guanylate cyclase (sGC), a heterodimer composed of α and β subunits, synthesizes cGMP in response to nitric oxide (NO). NO modulates vascular tone and structure but the relative contributions of cGMP-dependent versus cGMP-independent mechanisms remain uncertain. We studied the response to vascular injury in male (M) and female (F) mice with targeted deletion of exon 6 of the sGCα1 subunit (sGCα1-/-), resulting in a non-functional heterodimer. Methods: We measured aortic cGMP levels and mRNA transcripts encoding sGC α1, α2, and β1 subunits in wild type (WT) and sGCa1-/- mice. To study the response to vascular injury, BrdU-incorporation and neointima formation (maximum intima to media (I/M) ratio) were determined 5 and 28 days after carotid artery ligation, respectively. Results: Aortic cGMP levels were 4-fold higher in F than in M mice in both genotypes, and, within each gender, 4-fold higher in WT than in sGCa1-/-. In contrast, sGCα1, sGCα2, and sGCβ1 mRNA expression did not differ between groups. 3H-thymidine incorporation in cultured sGCa1-/- smooth muscle cells (SMC) was 27%±12% lower than in WT SMC and BrdU-incorporation in carotid arteries 5 days after ligation was significantly less in sGCa1-/- M than in WT M. Neointima area and I/M 28 days after ligation were 65% and 62% lower in sGCa1-/- M than in WT M mice (p<0,05 for both) but were not different in F mice. Conclusion: Functional deletion of sGCa1 resulted in reduced cGMP levels in male sGCa1-/- mice and a gender-specific effect on the adaptive response to vascular injury
Variation in ligand binding specificities of a novel class of poxvirus-encoded tumor necrosis factor-binding protein
Soluble guanylate cyclase is essential for the pulmonary but not the systemic vasodilator response to NO and limits pulmonary vascular remodeling in response to chronic hypoxia
Tenfold dose reduction of the in vivo cancer-destroying dose of TNF using combination therapies with PI3K inhibitors or NKT activators
Soluble guanylate cyclase deficiency selectively abolishes NO-mediated pulmonary vasodilation and increases the pulmonary vascular remodeling response to chronic hypoxia
The Role of Soluble Guanylyl Cyclase in Chronic Obstructive Pulmonary Disease
Rationale: 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.
Objectives: To determine the expression and function of sGC in patients
with COPD and in a murine model of COPD.
Methods: Expression of sGC alpha 1, alpha 2, and beta 1 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.
Measurements and Main Results: 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. sGC alpha 1(-/-)
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.
Conclusions: Down-regulation of sGC because of CS exposure might
contribute to airflow limitation in COPD