Abstract:
: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.
journal_name
Proc Natl Acad Sci U S Aauthors
Melichar VO,Behr-Roussel D,Zabel U,Uttenthal LO,Rodrigo J,Rupin A,Verbeuren TJ,Kumar H S A,Schmidt HHdoi
10.1073/pnas.0405509101keywords:
subject
Has Abstractpub_date
2004-11-23 00:00:00pages
16671-6issue
47eissn
0027-8424issn
1091-6490pii
0405509101journal_volume
101pub_type
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