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      Vascular Protective Effects of Xanthotoxin and Its Action Mechanism in Rat Aorta and Human Vascular Endothelial Cells


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          Objective: Xanthotoxin (XAT) is a linear furanocoumarin mainly extracted from the plants Ammi majus L. XAT has been reported the apoptosis of tumor cells, anti-convulsant, neuroprotective effect, antioxidative activity, and vasorelaxant effects. This study aimed to investigate the vascular protective effects and underlying molecular mechanisms of XAT. Methods: XAT’s activity was studied in rat thoracic aortas, isolated with aortic rings, and human umbilical vein endothelial cells (HUVECs). Results: XAT induced endothelium-dependent vasodilation in a concentration-dependent manner in the isolated rat thoracic aortas. Removal of endothelium or pretreatment of aortic rings with L-NAME, 1 H-[1,2,4]-oxadiazolo-[4,3- a]-quinoxalin-1-one, and wortmannin significantly inhibited XAT-induced relaxation. In addition, treatment with thapsigargin, 2-aminoethyl diphenylborinate, Gd<sup>3+</sup>, and 4-aminopyridine markedly attenuated the XAT-induced vasorelaxation. XAT increased nitric oxide production and Akt- endothelial NOS (eNOS) phosphorylation in HUVECs. Moreover, XAT attenuated the expression of TNF-α-induced cell adhesion molecules such as intercellular adhesion molecule, vascular cell adhesion molecule-1, and E-selectin. However, this effect was attenuated by the eNOS inhibitors L-NAME and asymmetric dimethylarginine. Conclusions: This study suggests that XAT induces vasorelaxation through the Akt-eNOS-cGMP pathway by activating the K<sub>V</sub> channel and inhibiting the L-type Ca<sup>2+</sup> channel. Furthermore, XAT exerts an inhibitory effect on vascular inflammation, which is correlated with the observed vascular protective effects.

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          Most cited references34

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          Endothelial Function and Dysfunction: Testing and Clinical Relevance

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            Endothelial nitric oxide synthase in vascular disease: from marvel to menace.

            Nitric oxide (NO*) is an important protective molecule in the vasculature, and endothelial NO* synthase (eNOS) is responsible for most of the vascular NO* produced. A functional eNOS oxidizes its substrate L-arginine to L-citrulline and NO*. This normal function of eNOS requires dimerization of the enzyme, the presence of the substrate L-arginine, and the essential cofactor (6R)-5,6,7,8-tetrahydro-L-biopterin (BH4), one of the most potent naturally occurring reducing agents. Cardiovascular risk factors such as hypertension, hypercholesterolemia, diabetes mellitus, or chronic smoking stimulate the production of reactive oxygen species in the vascular wall. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases represent major sources of this reactive oxygen species and have been found upregulated and activated in animal models of hypertension, diabetes, and sedentary lifestyle and in patients with cardiovascular risk factors. Superoxide (O2*-) reacts avidly with vascular NO* to form peroxynitrite (ONOO-). The cofactor BH4 is highly sensitive to oxidation by ONOO-. Diminished levels of BH4 promote O2*- production by eNOS (referred to as eNOS uncoupling). This transformation of eNOS from a protective enzyme to a contributor to oxidative stress has been observed in several in vitro models, in animal models of cardiovascular diseases, and in patients with cardiovascular risk factors. In many cases, supplementation with BH4 has been shown to correct eNOS dysfunction in animal models and patients. In addition, folic acid and infusions of vitamin C are able to restore eNOS functionality, most probably by enhancing BH4 levels as well.
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              Activation of endothelial nitric oxide synthase by cilostazol via a cAMP/protein kinase A- and phosphatidylinositol 3-kinase/Akt-dependent mechanism.

              We investigated the effect of cilostazol on nitric oxide (NO) production in human aortic endothelial cells (HAEC). Cilostazol increased NO production in a concentration-dependent manner, and NO production was also increased by other cyclic-AMP (cAMP)-elevating agents (forskolin, cilostamide, and rolipram). Cilostazol increased intracellular cAMP level, and that effect was enhanced in the presence of forskolin. In Western blot analysis, cilostazol increased phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser(1177) and of Akt at Ser(473) and dephosphorylation of eNOS at Thr(495). Cilostazol's regulation of eNOS phosphorylation was reversed by protein kinase A inhibitor peptide (PKAI) and by LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor. Moreover, the cilostazol-induced increase in NO production was inhibited by PKAI, LY294002, and N(G)-nitro-l-arginine methyl ester hydrochloride (l-NAME), a NOS inhibitor. In an in vitro model of angiogenesis, cilostazol-enhanced endothelial tube formation, an effect that was completely attenuated by inhibitors of PKA, PI3K, and NOS. These results suggest that cilostazol induces NO production by eNOS activation via a cAMP/PKA- and PI3K/Akt-dependent mechanism and that this effect is involved in capillary-like tube formation in HAEC.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                November 2020
                29 July 2020
                : 57
                : 6
                : 313-324
                [_a] aDepartment of Pharmacology, Yanbian University Medical College, Jilin, China
                [_b] bHanbang Cardio-Renal Syndrome Research Center, Wonkwang University, Iksan, Republic of Korea
                [_c] cCollege of Oriental Medicine and Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Republic of Korea
                [_d] dCollege of Pharmacy, Yanbian University, Jilin, China
                [_e] eDepartment of Anatomy, Yanbian University Medical College, Jilin, China
                Author notes
                *Yun Jung Lee, Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, 460, Iksan-daero, Iksan 54538 (Republic of Korea), shrons@wku.ac.kr, , Yu Jin, Department of Anatomy, Yanbian University Medical College Yianji, Jilin, 133002 (China), jinyu@ybu.edu.cn
                509112 J Vasc Res 2020;57:313–324
                © 2020 S. Karger AG, Basel

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                Page count
                Figures: 6, Tables: 1, Pages: 12
                Research Article

                General medicine,Neurology,Cardiovascular Medicine,Internal medicine,Nephrology
                Inflammation,Vasodilation,Cell adhesion molecule,Endothelial nitric oxide synthase,Xanthotoxin


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