Reduced cGMP signaling associated with neointimal proliferation and vascular dysfunction in late-stage atherosclerosis

doi:10.1073/pnas.0405509101

Reduced cGMP signaling associated with neointimal proliferation and vascular dysfunction in late-stage atherosclerosis

^*Department of Pharmacology and Toxicology, Julius-Maximilians-Universität, Versbacher Strasse 9, D-97078 Würzburg, Germany; ^†Division of Angiology, Servier Research Institute, 11, Rue des Moulineaux, F-92150 Suresnes, France; ^‡Department of Comparative Neuroanatomy, Instituto Cajal, Avenida del Doctor Arce 37, E-28002 Madrid, Spain; and ^§Rudolf Buchheim Institute for Pharmacology, Frankfurter Strasse 107, 35392 Giessen, Germany

Edited by Louis J. Ignarro, University of California School of Medicine, Los Angeles, CA, and approved October 7, 2004 (received for review July 30, 2004)

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.

Footnotes

↵ ¶ To whom correspondence should be addressed. E-mail: kumar.arun{at}pharma.med.unigiessen.de.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: cGK, cGMP-dependent protein kinase I; NOS, NO synthase; NT, nitrotyrosine; PDE, phosphodiesterase; sGC, soluble guanylyl cyclase; SNP, sodium nitroprusside; SOD, superoxide dismutase; VASP, vasodilator-stimulated phosphoprotein; P_Ser-239-VASP, VASP phosphorylated at Ser-239.