Zhekang Ying1, Xiaoyun Xie2, Minjie Chen3, Kevin Yi4, Sanjay Rajagopalan4. 1. Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, PR China; Department of Medicine Cardiology Division, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Electronic address: yingzhekang@hotmail.com. 2. Division of Geriatric Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, PR China. 3. Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, PR China; Department of Medicine Cardiology Division, University of Maryland School of Medicine, Baltimore, MD 21201, USA. 4. Department of Medicine Cardiology Division, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Abstract
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.
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.
Authors: D Fulton; J P Gratton; T J McCabe; J Fontana; Y Fujio; K Walsh; T F Franke; A Papapetropoulos; W C Sessa Journal: Nature Date: 1999-06-10 Impact factor: 49.962
Authors: Wright Jones; Xia Li; Zhi-chao Qu; Laureta Perriott; Richard R Whitesell; James M May Journal: Free Radic Biol Med Date: 2002-07-01 Impact factor: 7.376