Lipoic acid attenuates the expression of adhesion molecules by increasing endothelial nitric-oxide synthase activity

Jin, Hongbo; Yang, Yongbin; Song, Ye; Zhang, Yongchun; Li, Yurong

doi:10.1007/s11033-012-2071-4

Cited by 13 publications

(9 citation statements)

References 34 publications

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“…Consistently, LA increases NO release by HUVECs (Figure 2) and nitrite/nitrate production in living animals (Figure 4). Our results are consistent with several studies showing that LA increases eNOS activity [13–15], suggesting that this action of LA may be pharmacologically important. In addition to phosphorylation/de-phosphorylation, other post-translational modifications such as protein-protein interaction and the bioavailability of coenzyme tetrahydrobiopterin (BH4) also play a role in regulation of eNOS activity [12, 16, 17].…”

Section: Discussionsupporting

confidence: 93%

“…In addition to our results, several other studies have shown that LA increases eNOS activity in both cultured cells and living animals [13–15, 22, 29, 30], suggesting that LA may exert its therapeutic effects on those cardiovascular diseases through targeting eNOS. Although in the majority of those studies it is postulated that eNOS activation by LA is subsequent to its antioxidant action, direct evidence of this is lacking.…”

Section: Discussionsupporting

confidence: 82%

“…Notably, several studies have demonstrated that LA increases eNOS activity [13–15], providing a potential mechanism that can explain its therapeutic effects on cardiovascular diseases. However, how LA activates eNOS remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Alpha-lipoic acid activates eNOS through activation of PI3-kinase/Akt signaling pathway

Zhao

Xie

Chen

et al. 2015

Vascular Pharmacology

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Background Lipoic acid (LA) exerts therapeutic effects on cardiovascular diseases. However, the mechanisms underlying these therapeutic effects remain elusive. Endothelial nitric oxide synthase (eNOS) plays a critical role in cardiovascular homeostasis. LA was shown to potently activate PI3-kinase/Akt pathway, and the latter is critical in the regulation of eNOS activity. In the present study, we test the hypothesis that LA improves endothelial function through PI3-kinase/Akt-mediated eNOS activation. Methods and Results Western blot analysis showed that LA time- and dose-dependently induced phosphorylation of Akt and eNOS in human umbilical vein endothelial cells (HUVECs). Both PI3-kinase and Akt inhibitors abolished LA-induced eNOS phosphorylation, indicating that LA induces eNOS phosphorylation through the PI3-kinase/Akt pathway. This increase in eNOS phosphorylation was paralleled by an increase in NO release by HUVECs, supporting its relevance in eNOS activity regulation. Myograph analysis revealed that LA relaxed phenylephrine-induced contraction. Endothelium removal and NOS inhibition by L-NAME abolished this vasodilator action of LA, and Akt but not AMPK inhibition significantly reduced the vasodilator action of LA, indicating that it is mediated by PI3-kinase/Akt pathway-dependent activation of eNOS. Consistent with in vitro results, intraperitoneal injection with LA significantly increased plasma nitrite and nitrate levels in C57Bl/6j mice. Conclusions LA activates eNOS through a PI3-kinase/Akt signaling pathway-dependent mechanism, offering a potential molecular basis for the therapeutic effects of LA on cardiovascular diseases.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 82%

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Alpha-lipoic acid activates eNOS through activation of PI3-kinase/Akt signaling pathway

Zhao

Xie

Chen

et al. 2015

Vascular Pharmacology

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“…Nonetheless, the synergistic NO increase due to concurrent administration of α-lipoic acid and CSA is in line with reports showing that CSA (López-Ongil et al, 1998) and α-lipoic acid (Jin et al, 2013) increase nitric oxide synthase (NOS) activity. Further, NO production increases in inflamed colon due to non-enzymatic reaction of hydrogen peroxide (H 2 O 2 ) with arginine (Zhang et al, 1999).…”

Section: Discussionsupporting

confidence: 86%

Co-administration of α-lipoic acid and cyclosporine aggravates colon ulceration of acetic acid-induced ulcerative colitis via facilitation of NO/COX-2/miR-210 cascade

El‐Gowelli

Saad

Abdel-Galil

et al. 2015

Toxicology and Applied Pharmacology

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“…Low NO bioavailability has been shown to promote platelet activation [35], [36], [37] and to increase cellular adhesion [38], [39], [40]. Inhibition of endothelial nitric oxide synthase (eNOS) with L-NG-monomethyl Arginine citrate (L-NAME) increased leukocyte rolling and adhesion [41].…”

Section: Introductionmentioning

confidence: 99%

Potential therapeutic action of nitrite in sickle cell disease

et al. 2017

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Sickle cell disease is caused by a mutant form of hemoglobin that polymerizes under hypoxic conditions, increasing rigidity, fragility, calcium influx-mediated dehydration, and adhesivity of red blood cells. Increased red cell fragility results in hemolysis, which reduces nitric oxide (NO) bioavailability, and induces platelet activation and inflammation leading to adhesion of circulating blood cells. Nitric Oxide inhibits adhesion and platelet activation. Nitrite has emerged as an attractive therapeutic agent that targets delivery of NO activity to areas of hypoxia through bioactivation by deoxygenated red blood cell hemoglobin. In this study, we demonstrate anti-platelet activity of nitrite at doses achievable through dietary interventions with comparison to similar doses with other NO donating agents. Unlike other NO donating agents, nitrite activity is shown to be potentiated in the presence of red blood cells in hypoxic conditions. We also show that nitrite reduces calcium associated loss of phospholipid asymmetry that is associated with increased red cell adhesion, and that red cell deformability is also improved. We show that nitrite inhibits red cell adhesion in a microfluidic flow-channel assay after endothelial cell activation. In further investigations, we show that leukocyte and platelet adhesion is blunted in nitrite-fed wild type mice compared to control after either lipopolysaccharide- or hemolysis-induced inflammation. Moreover, we demonstrate that nitrite treatment results in a reduction in adhesion of circulating blood cells and reduced red blood cell hemolysis in humanized transgenic sickle cell mice subjected to local hypoxia. These data suggest that nitrite is an effective anti-platelet and anti-adhesion agent that is activated by red blood cells, with enhanced potency under physiological hypoxia and in venous blood that may be useful therapeutically.

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Lipoic acid attenuates the expression of adhesion molecules by increasing endothelial nitric-oxide synthase activity

Cited by 13 publications

References 34 publications

Alpha-lipoic acid activates eNOS through activation of PI3-kinase/Akt signaling pathway

Alpha-lipoic acid activates eNOS through activation of PI3-kinase/Akt signaling pathway

Co-administration of α-lipoic acid and cyclosporine aggravates colon ulceration of acetic acid-induced ulcerative colitis via facilitation of NO/COX-2/miR-210 cascade

Potential therapeutic action of nitrite in sickle cell disease

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