Background and purpose: Aortic complications account for the major mortality in Marfan syndrome (MFS), a connective tissue disorder caused by mutations in FBN1 encoding fibrillin-1. We hypothesized that MFS impaired endothelial function and nitric oxide (NO) production in the aorta. Experimental approach: Mice (at 3, 6, 9 and 12 months of age) heterozygous for the Fbn1 allele encoding a cysteine substitution (Fbn1 C1039G/ þ , Marfan mice, n ¼ 75), the most common class of mutation in MFS, were compared with agematched control littermates (n ¼ 75). Thoracic and abdominal aortas from the two groups were studied. Key results: Isometric force measurements revealed that relaxation to ACh (but not to sodium nitroprusside) was diminished in the phenylephrine-precontracted Marfan thoracic aorta at 6 months of age (pEC 50 ¼ 6.1270.22; maximal response, E max ¼ 52.776.8%; control: pEC 50 ¼ 7.3470.19; E max ¼ 84.872.2%). At one year, both inhibition of NO production with N onitro-L-arginine methyl ester, or denudation of endothelium increased the phenylephrine-stimulated contraction in the control thoracic aorta by 35%, but had no effect in the Marfan aorta, indicating a loss of basal NO production in the Marfan vessel. From 6 months, a reduced phosphorylation of endothelial NOS (eNOS) Ser1177 and Akt Thr308 detected by Western blotting was observed in the Marfan thoracic aorta, which was accompanied by decreased levels of cGMP. Expressions of Akt and eNOS in the abdominal aorta were not different between the two groups. Conclusions and Implications: MFS impairs endothelial function and signaling of NO production in the thoracic aorta, suggesting the importance of NO in the age-related progression of thoracic aortic manifestations.

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The family of nitric oxide synthases (NOS) has significant importance in various physiological mechanisms and is also involved in many pathological processes. Three NOS isoforms have been identified: neuronal NOS (nNOS or NOS 1), endothelial NOS (eNOS or NOS 3), and an inducible NOS (iNOS or NOS 2). Both nNOS and eNOS are constitutively expressed. Classically, eNOS is considered the main isoform involved in the control of the vascular function. However, more recent studies have shown that nNOS is present in the vascular endothelium and importantly contributes to the maintenance of the homeostasis of the cardiovascular system. In physiological conditions, besides nitric oxide (NO), nNOS also produces hydrogen peroxide (H2O2) and superoxide (O2•-) considered as key mediators in non-neuronal cells signaling. This mini-review highlights recent scientific releases on the role of nNOS in vascular homeostasis and cardiovascular disorders such as hypertension and atherosclerosis.

Capettini LS, Cortes SF, Gomes MA, Silva GA, Pesquero JL, Lopes MJ, Teixeira MM, Lemos VS. Neuronal nitric oxide synthasederived hydrogen peroxide is a major endothelium-dependent relaxing factor. Am J Physiol Heart Circ Physiol 295: H2503-H2511, 2008. First published October 24, 2008 doi:10.1152/ajpheart.00731.2008.-Endothelium-dependent vasorelaxation in large vessels is mainly attributed to N -nitro-L-arginine methyl ester (L-NAME)-sensitive endothelial nitric oxide (NO) synthase (eNOS)-derived NO production. Endothelium-derived hyperpolarizing factor (EDHF) is the component of endothelium-dependent relaxations that resists full blockade of NO synthases (NOS) and cyclooxygenases. H2O2 has been proposed as an EDHF in resistance vessels. In this work we propose that in mice aorta neuronal (n)NOS-derived H2O2 accounts for a large proportion of endothelium-dependent ACh-induced relaxation. In mice aorta rings, ACh-induced relaxation was inhibited by L-NAME and N -nitro-L-arginine (L-NNA), two nonselective inhibitors of NOS, and attenuated by selective inhibition of nNOSNO2 -L-Dbu) and 1-(2-trifluoromethylphehyl)imidazole (TRIM). The relaxation induced by ACh was associated with enhanced H2O2 production in endothelial cells that was prevented by the addition of L-NAME, L-NNA, L-Arg NO2 -L-Dbu, TRIM, and removal of the endothelium. The addition of catalase, an enzyme that degrades H2O2, reduced ACh-dependent relaxation and abolished ACh-induced H2O2 production. RT-PCR experiments showed the presence of mRNA for eNOS and nNOS but not inducible NOS in mice aorta. The constitutive expression of nNOS was confirmed by Western blot analysis in endothelium-containing vessels but not in endothelium-denuded vessels. Immunohistochemistry data confirmed the localization of nNOS in the vascular endothelium. Antisense knockdown of nNOS decreased both ACh-dependent relaxation and ACh-induced H2O2 production. Antisense knockdown of eNOS decreased ACh-induced relaxation but not H2O2 production. Residual relaxation in eNOS knockdown mouse aorta was further inhibited by the selective inhibition of nNOS with L-Arg NO2 -L-Dbu. In conclusion, these results show that nNOS is constitutively expressed in the endothelium of mouse aorta and that nNOS-derived H2O2 is a major endothelium-dependent relaxing factor. Hence, in the mouse aorta, the effects of nonselective NOS inhibitors cannot be solely ascribed to NO release and action without considering the coparticipation of H2O2 in mediating vasodilatation. vasorelaxation; acetylcholine; antisense; knockdown NEURONAL NITRIC OXIDE (NO) synthase (nNOS) is a Ca 2ϩ / calmodulin-dependent isoform of NO synthase (NOS) constitutively expressed in neurons and in many other different tissues (17,32,36,50,57). In the cardiovascular system, nNOS is expressed in vascular smooth muscle cells (6, 7), vascular endothelium (1, 23), and cardiac myocytes (53). nNOS has a physiologically relevant role in modulating cardiac function (10), myogenic tone (16), systemic arterial pressure (28), and cerebral blood ...

Hancornia speciosa has a potential anti-diabetic effect through a mechanism dependent on inhibition of α-glucosidase and increase on glucose uptake. These results give support to the use on traditional medicine of this medicinal plant.