Proatherosclerotic Effect of the α1-Subunit of Soluble Guanylyl Cyclase by Promoting Smooth Muscle Phenotypic Switching.
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 β 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.
Institute for Integrative and Experimental Genomics, University of Lübeck, DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, University Heart Centre Lübeck, Lübeck, Germany.
Maria
M
Segura-Puimedon
Department of Pharmacology, Ruhr-University Bochum, Bochum, Germany.
Evanthia
E
Mergia
Institute for Integrative and Experimental Genomics, University of Lübeck, DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, University Heart Centre Lübeck, Lübeck, Germany.
Jaafar
J
Al-Hasani
Institute for Integrative and Experimental Genomics, University of Lübeck, DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, University Heart Centre Lübeck, Lübeck, Germany.
Redouane
R
Aherrahrou
Institute for Integrative and Experimental Genomics, University of Lübeck, DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, University Heart Centre Lübeck, Lübeck, Germany.
Stephanie
S
Stoelting
Institute for Integrative and Experimental Genomics, University of Lübeck, DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, University Heart Centre Lübeck, Lübeck, Germany.
Felix
F
Kremer
Institute for Integrative and Experimental Genomics, University of Lübeck, DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, University Heart Centre Lübeck, Lübeck, Germany.
Jennifer
J
Freyer
Department of Pharmacology, Ruhr-University Bochum, Bochum, Germany.
Doris
D
Koesling
Institute for Integrative and Experimental Genomics, University of Lübeck, DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, University Heart Centre Lübeck, Lübeck, Germany.
Jeanette
J
Erdmann
German Heart Center, Technical University of Munich, DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.
Heribert
H
Schunkert
Department of Physiology, University of Lübeck, DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, University Heart Centre Lübeck, Lübeck, Germany.
Cor
C
de Wit
Institute for Integrative and Experimental Genomics, University of Lübeck, DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, University Heart Centre Lübeck, Lübeck, Germany. Electronic address: zouhair.aherrahrou@iieg.uni-luebeck.de.
Zouhair
Z
Aherrahrou
D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005260:Female; D005838:Genotype; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D000071756:Soluble Guanylyl Cyclase / Q000235:genetics / Q000378:metabolism*
C000605668:Gucy1a3 protein, mouse; D000071756:Soluble Guanylyl Cyclase