Reduced cGMP signaling associated with neointimal proliferation and vascular dysfunction in late-stage atherosclerosis.
Atherosclerosis is associated with alterations in nitric oxide (NO)/cGMP signaling. In early stages of the disease, inflammatory and possibly other cells produce reactive oxygen species that scavenge vasoprotective NO. In addition to the oxidative stress, expression and activity of enzymes downstream to NO formation may also be affected. Here, we show in the aortas of chronically hypercholesterolemic rabbits (a model of late-stage atherosclerosis), both subunits and specific activity of the NO receptor soluble guanylyl cyclase (sGC) were significantly reduced, whereas overall NO synthase activity was unaffected. These changes were most prominent in the neointimal layer, wherein cGMP-dependent protein kinase I (cGK) levels also were reduced. Additionally, a protein (p38(nt)) that was constitutively tyrosine-nitrated was detected, and its expression was significantly reduced in atherosclerotic aorta. Phosphorylation of the cGK substrate vasodilator-stimulated phosphoprotein (VASP) at Ser-239, an established biochemical endpoint of NO/cGMP signaling, also was reduced. Thus, late-stage atherosclerosis is associated not only with enhanced NO breakdown but also with altered NO reception and cGMP signaling. Preferential down-regulation in neointima suggests a direct connection of these changes to neointimal proliferation and vascular dysfunction and provides a rationale for future pharmacotherapy using classical and novel sGC activators.
Melichar
Volker O
VO
Department of Pharmacology and Toxicology, Julius-Maximilians-Universität, Versbacher Strasse 9, D-97078 Würzburg, Germany.
Behr-Roussel
Delphine
D
Zabel
Ulrike
U
Uttenthal
L Otto
LO
Rodrigo
José
J
Rupin
Alain
A
Verbeuren
Tony J
TJ
Kumar H S
Arun
A
Schmidt
Harald H H W
HH
D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology / Q000503:physiopathology; D001161:Arteriosclerosis / Q000473:pathology* / Q000503:physiopathology*; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000502:physiology; D006152:Cyclic GMP / Q000502:physiology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008840:Microfilament Proteins; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D030421:Peroxynitrous Acid / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry / Q000502:physiology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D011817:Rabbits; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism; D000098662:Vasodilator-Stimulated Phosphoprotein
D015815:Cell Adhesion Molecules; D008055:Lipids; D008840:Microfilament Proteins; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D013482:Superoxide Dismutase; D017869:Cyclic GMP-Dependent Protein Kinases; D010727:Phosphoric Diester Hydrolases; D006162:Guanylate Cyclase; D006152:Cyclic GMP