Proatherosclerotic Effect of the α1-Subunit of Soluble Guanylyl Cyclase by Promoting Smooth Muscle Phenotypic Switching.
Am J Pathol
; 186(8): 2220-2231, 2016 08.
Article
em En
| MEDLINE
| ID: mdl-27315776
ABSTRACT
Soluble guanylate cyclase (sGC), a key enzyme of the nitric oxide signaling pathway, is formed as a heterodimer by various isoforms of its α and ß subunit. GUCY1A3, encoding the α1 subunit, was identified as a risk gene for coronary artery disease and myocardial infarction, but its specific contribution to atherosclerosis remains unclear. This study sought to decipher the role of Gucy1a3 in atherosclerosis in mice. At age 32 weeks and after 20 weeks of standard or high-fat diet, Gucy1a3(-/-)/Ldlr(-/-) mice exhibited a significant reduction of the atherosclerotic plaque size at the aortic root and the aorta for high-fat diet animals as compared with Ldlr(-/-) control mice. Collagen content in plaques in the aortic root was reduced, suggesting an alteration of smooth muscle cell function. Proliferation and migration were reduced in Gucy1a3(-/-) primary aortic smooth muscle cells (AoSMCs), and proliferation was also reduced in human AoSMCs after inhibition of sGC by 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one. Gucy1a3 deficiency in AoSMCs prevents their phenotypic switching, as indicated by the differential expression of marker proteins. The inherited Gucy1a3(-/-) loss exerts an atheroprotective effect. We suggest that sGC activity promotes the phenotypic switching of smooth muscle cells from a contractile to a synthetic state, fostering the formation of atherosclerosis. Preventing this switch by sGC inhibition may provide a novel target in atherosclerotic disease.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Miócitos de Músculo Liso
/
Aterosclerose
/
Guanilil Ciclase Solúvel
/
Músculo Liso Vascular
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Alemanha