| Research Abstract |
Background :
Nitric oxide (NO) has multiple important actions that contribute to the maintenance of vascular homeostasis. NO is synthesized by three different isoforms of NO synthase (NOS), all of which have been reported to be expressed in human atherosclerotic vascular lesions. Although the regulatory roles of endothelial NOS (eNOS) and inducible NOS (iNOS) on the development of atherosclerosis have been described, little is known about the role of neuronal NOS (nNOS). We recently demonstrated that nNOS also exerts important vasculoprotective effects in vivo. In this study, we examined the molecular mechanisms for vascular nNOS expression.
Methods and Results :
1.In a mouse carotid artery ligation model and a rat balloon injury model, nNOS was expressed in vascular wall cells after vascular injury.
2.In cultured rat aortic smooth muscle cells, angiotensin II and lnterleukin-1β increased nNOS expression at both mRNA and protein levels. These increases in nNOS expression were inhibited by pretreatment with the nuclear factor-kappa B (NE-kB) inhibitor.
3.Platelet-derived growth factor (PDGF) also enhanced nNOS expression at both mRNA and protein levels in cultured rat aortic smooth muscle cells, which were abolished by the mitogen-activated protein (MAP) kinase (MEK) inhibitor (PD98059/U0126) and by gene transfer of dominant negative type of MEK. Importantly, gene transfer of wild-type of MEK itself elicited nNOS induction in the absence of PDGF in the cells.
Conclusions :
We were able to demonstrate that nNOS is up-regulated in vascular lesions after vascular injury, that nNOS is induced in vascular smooth muscle cells by inflammatory/proliferative stimuli, such as angiotensin II, interleukin-1β, or PDGF, and that the NE-kB and MAP kinase pathways play important roles in the vascular nNOS induction. Our findings provide a novel concept that nNOS is subject to expressional regulation in the vascular system, while it is constitutively expressed in the nervous system.
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