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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.
Highlights
The endothelium is a monolayered continuous cell sheet lining the luminal surface of vessel walls that serves as the cross-bridge of communication between the blood and cells and actively regulates the functions of surrounding cells through complex signaling pathways [1,2]. Under certain circumstances, such as hypercholesterolemia and atherosclerosis, modified LDL impairs the function of the endothelial nitric oxide synthase/nitric oxide (NO) system and upregulates the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in endothelial cell (ECs), leading to the recruitment of monocytes into the subendothelial space of the vessel wall [3,4]
Our results demonstrated that TECC promotes NO production via the Akt/calmodulin kinase II (CaMKII)/AMPK/endothelial nitric oxide synthase (eNOS) signaling cascade, which inhibits the inflammatory responses, and retards the progression of atherosclerosis
To test whether TCEE can activate the eNOS/NO signaling pathway, endothelial cells (ECs) were treated with the indicated concentrations (0.125, 0.25, 0.5, 1, 2, 4, and 8 μg/mL) of TCEE, and the effects of TCAE on cell viability and NO production were
Summary
The endothelium is a monolayered continuous cell sheet lining the luminal surface of vessel walls that serves as the cross-bridge of communication between the blood and cells and actively regulates the functions of surrounding cells through complex signaling pathways [1,2] Under certain circumstances, such as hypercholesterolemia and atherosclerosis, modified LDL impairs the function of the endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) system and upregulates the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in endothelial cell (ECs), leading to the recruitment of monocytes into the subendothelial space of the vessel wall [3,4]. We investigated effects of TCEE and the related molecular mechanisms underlying the activation of eNOS-NO signaling, and we ascertained whether TCEE-mediated enhancement of NO bioavailability contributes to its anti-inflammatory property against inflammatory responses. Our results demonstrated that TECC promotes NO production via the Akt/CaMKII/AMPK/eNOS signaling cascade, which inhibits the inflammatory responses, and retards the progression of atherosclerosis
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