Endothelial Nitric Oxide Mediates the Anti-Atherosclerotic Action of Torenia concolor Lindley var. Formosama Yamazaki

Abstract

Torenia concolor Lindley var. formosama Yamazaki ethanolic extract (TCEE) is reported to have anti-inflammatory and anti-obesity properties. However, the effects of TCEE and its underlying mechanisms in the activation of endothelial nitric oxide synthase (eNOS) have not yet been investigated. Increasing the endothelium-derived nitric oxide (NO) production has been known to be beneficial against the development of cardiovascular diseases. In this study, we investigated the effect of TCEE on eNOS activation and NO-related endothelial function and inflammation by using an in vitro system. In endothelial cells (ECs), TCEE increased NO production in a concentration-dependent manner without affecting the expression of eNOS. In addition, TCEE increased the phosphorylation of eNOS at serine 635 residue (Ser635) and Ser1179, Akt at Ser473, calmodulin kinase II (CaMKII) at threonine residue 286 (Thr286), and AMP-activated protein kinase (AMPK) at Thr172. Moreover, TCEE-induced NO production, and EC proliferation, migration, and tube formation were diminished by pretreatment with LY294002 (an Akt inhibitor), KN62 (a CaMKII inhibitor), and compound C (an AMPK inhibitor). Additionally, TCEE attenuated the tumor necrosis factor-α-induced inflammatory response as evidenced by the expression of adhesion molecules in ECs and monocyte adhesion onto ECs. These inflammatory effects of TCEE were abolished by L-NG-nitroarginine methyl ester (an NOS inhibitor). Moreover, chronic treatment with TCEE attenuated hyperlipidemia, systemic and aortic inflammatory response, and the atherosclerotic lesions in apolipoprotein E-deficient mice. Collectively, our findings suggest that TCEE may confer protection from atherosclerosis by preventing endothelial dysfunction.

Hyperuricemia induces endothelial dysfunction and accelerates atherosclerosis by disturbing the asymmetric dimethylarginine/dimethylarginine dimethylaminotransferase 2 pathway

“…EC dysfunction characterized by a reduction of NO bioavailability and induction of adhesion molecules is the primary event in the initiation of atherosclerosis [ 18 , 19 ]. Prevention of EC dysfunction by activating eNOS–NO signaling is suggested to be the key mechanism that allows clinical reagents to be used in treating cardiovascular diseases [ 19 ].…”

“…EC dysfunction characterized by a reduction of NO bioavailability and induction of adhesion molecules is the primary event in the initiation of atherosclerosis [ 18 , 19 ]. Prevention of EC dysfunction by activating eNOS–NO signaling is suggested to be the key mechanism that allows clinical reagents to be used in treating cardiovascular diseases [ 19 ]. For example, in addition to reducing lipid levels, statins activate eNOS and promote NO production; this suppresses the vascular inflammatory response, thereby reducing cardiovascular risks in patients [ 35 ].…”

“…For example, in addition to reducing lipid levels, statins activate eNOS and promote NO production; this suppresses the vascular inflammatory response, thereby reducing cardiovascular risks in patients [ 35 ]. By contrast, eNOS–NO signaling impairment induces EC dysfunction and results in vascular inflammation, which leads to atherosclerosis progression [ [18] , [19] , [20] , [21] , [22] , [23] , [24] ]. Our findings support the hypothesis that excess uric acid induces EC dysfunction by reducing NO production and increasing ICAM-1 and VCAM-1 expression and monocyte adhesion to ECs.…”

“…Endothelium not only serves as the cross-bridge of communication between blood and cells but also actively regulates the processes and functions of surrounding cells through complex signaling pathways [ [15] , [16] , [17] ]. Particularly, endothelium-derived nitric oxide (NO) plays a key role in the regulation of vascular tone, modulation of inflammation, inhibition of vascular growth, platelet activation, and blood coagulation [ 18 , 19 ]. Disruption of endothelial function reduces the release of NO and causes increased vascular tone, enhanced inflammation, and proliferation of vascular smooth muscle cells, which all promote atherosclerosis progression [ [20] , [21] , [22] , [23] , [24] ].…”

Rutaecarpine Increases Nitric Oxide Synthesis via eNOS Phosphorylation by TRPV1-Dependent CaMKII and CaMKKβ/AMPK Signaling Pathway in Human Endothelial Cells

“…The transcription factor nuclear factor-κB (NF-κB) composed of p65 and p50 subunits is an important factor in the inflammatory response in endothelial cells, and eNOS-derived NO generation is closely related to anti-inflammatory effects [24,25]. To assess the association between the inflammatory signaling pathway and eNOS activation in endothelial cells under RUT treatment, we examined the effect of RUT on TNF-α-induced phosphorylation and translocation of NF-κB p65 in endothelial cells.…”