Role of Rho/Rho-kinase and NO/cGMP signaling pathways in vascular function prior to atherosclerosis.
OBJECTIVE
Atherosclerosis is a cardiovascular disease; however, there is little information on signal transduction for vascular function in the early stage of atherosclerosis. In this work, we investigated the role of Rho/Rho-kinase and nitrogen oxide (NO)/cyclic GMP (cGMP) signaling pathways in the aorta prior to atherosclerosis.


METHODS
Tension, the expression of RhoA protein, Rho-kinase activity and the cGMP level were measured using endothelium-intact or -denuded aorta prepared from apolipoprotein E-deficient (apoE-KO) and C57BL/6 wild-type (WT) mice at 2 months of age.


RESULTS
Phenylephrine (PE) induced less maximal contraction in the endothelium-denuded aorta from apoE-KO than from WT mice. A Rho-kinase inhibitor (Y-27632) reduced more effectively the contraction of apoE-KO than WT mice, but their RhoA proteins and Rho-kinase activities were not so different. Acetylcholine caused larger relaxation of the PE-stimulated, endothelium-intact aorta in apoE-KO due to endothelial NO release than WT mice. The basal cGMP level in the endothelium-intact aorta of apoE-KO mice was higher than that of WT.


CONCLUSIONS
Smooth muscle contraction via alpha(1)-adrenergic receptor shows higher dependency on Rho-kinase activity, suggesting down-regulation of the mechanism different from Rho/Rho kinase signaling in the aorta prior to atherosclerosis. Endothelium-dependent relaxation is also intensified through the NO/cGMP pathway.
Mori-Kawabe
Mayumi
M
Department of Cellular and Molecular Pharmacology, Nagoya City University Graduate School of Medical Sciences, Japan. mkawabe@med.nagoya-cu.ac.jp
Tsushima
Hiromi
H
Fujimoto
Seigo
S
Tada
Toyohiro
T
Ito
Jin-ichi
J
D000577:Amides / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology* / Q000378:metabolism* / Q000473:pathology; D006152:Cyclic GMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009119:Muscle Contraction; D009569:Nitric Oxide / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism*
D000577:Amides; D001057:Apolipoproteins E; D011725:Pyridines; C108830:Y 27632; D009569:Nitric Oxide; D054460:rho-Associated Kinases; D020741:rho GTP-Binding Proteins; D006152:Cyclic GMP