Molecular mechanisms of activation of endothelial nitric oxide synthase mediated by transient receptor potential vanilloid type 1

Ching, Li Chieh; Kou, Yu Ru; Shyue, Song Kun; Su, Kuo‐Hui; Wei, Jeng; Cheng, Li; Yu, Yuan Bin; Pan, Ching Chian; Lee, Tzong‐Shyuan

doi:10.1093/cvr/cvr104

Cited by 124 publications

(132 citation statements)

References 35 publications

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“…Moreover, our results regarding the non-LKB1 AMPKK function of CaMKII in TRPV1 ligand-induced activation of AMPK/eNOS signaling are consistent with previous studies of caffeine-elicited fatty acid uptake and oxidation, and puerarin-increased eNOS phosphorylation mediated through a CaMKII/AMPK signaling pathway (31,32). Recently, growing evidence has suggested that the TRPV1 channel plays an important role in the activation of eNOS activation and eNOS-related cardiovascular diseases such as hypertension and atherosclerosis (7,8). TRPV1 activation by capsaicin leads to increased phosphorylation of protein kinase A (PKA) and eNOS in ECs and improved vasorelaxation and reduced blood pressure in hypertensive rats (7 …”

Section: Discussionsupporting

confidence: 92%

“…This notion was further supported by our findings that in parallel to the eNOS activation, exposing ECs to evodiamine markedly increased the physical interaction of TRPV1 with eNOS and AMPK. Thus, apart from its channel function, TRPV1 may function as a scaffold for the recruitment and formation of a complex encompassing eNOS and kinases, and these proteinprotein interactions may also be critical for the regulation of eNOS activity, which agrees with our previous finding of TRPV1 ligands promoting the formation of the TRPV1-Akt-CaMKII-eNOS complex in ECs (8). These findings strongly indicate that kinase-dependent regulation and protein-protein interaction may work in concert to promote eNOS activation and NO production in response to TRPV1 ligands in ECs.…”

Section: A M P K I N T R P V 1 -M E D I a T E D E N O S A C T I Vsupporting

confidence: 91%

“…During the past decades, evodiamine, the main ingredient of the bioactive components of this fruit, had been found to account for the antiarrhythmic or hypotensive effect by prolonging the action-potential duration in cardiac cells or by inducing vascular relaxation (49,50). Notably, we recently demonstrated that evodiamine can induce an increase in NO bioavailability in ECs and confer protection from atherosclerosis in ApoE-deficient mice (8). In this study, we further confirmed that clinical relevance of TRPV1-AMPK signaling in evodiamine-mediated angiogenesis and atheroprotection.…”

Section: A M P K I N T R P V 1 -M E D I a T E D E N O S A C T I Vmentioning

confidence: 88%

“…Emerging evidence suggests that TRPV1 expressed in nonneuronal cells such as endothelial cells (ECs) may be an important sensor and regulator. Activation of TRPV1 by ligands increases endothelial nitric oxide synthase (eNOS) activity and NO production (6)(7)(8), both of which confer protection against certain cardiovascular diseases such as hypertension and stroke (9,10). However, the detailed mechanism underlying TRPV1-mediated activation of eNOS is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

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Implication of AMP-Activated Protein Kinase in Transient Receptor Potential Vanilloid Type 1-Mediated Activation of Endothelial Nitric Oxide Synthase

Ching

Chen

et al. 2012

Mol Med

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We investigated whether AMP-activated protein kinase (AMPK), a multifunctional regulator of energy homeostasis, is involved in transient receptor potential vanilloid type 1 (TRPV1)-mediated activation of endothelial nitric oxide synthase (eNOS) in endothelial cells (ECs) and mice. In ECs, treatment with evodiamine, the activator of TRPV1, increased the phosphorylation of AMPK, acetyl-CoA carboxylase (ACC) and eNOS, as revealed by Western blot analysis. Inhibition of AMPK activation by compound C or dominant-negative AMPK mutant abrogated the evodiamine-induced increase in phosphorylation of AMPK and eNOS and NO bioavailability, as well as tube formation in ECs. Immunoprecipitation and two-hybrid analysis demonstrated that AMPK mediated the evodiamine-induced increase in the formation of a TRPV1-eNOS complex. Additionally, TRPV1 activation by evodiamine increased the phosphorylation of AMPK and eNOS in aortas of wild-type mice but did not activate eNOS in aortas of TRPV1-deficient mice. In mice, inhibition of AMPK activation by compound C markedly decreased evodiamine-evoked angiogenesis in matrigel plugs and in a hind-limb ischemia model. Moreover, evodiamine-induced phosphorylation of AMPK and eNOS in aortas of apolipoprotein E-deficient (ApoE -/-) mice was abrogated in TRPV1-deficient ApoE -/-mice. In conclusion, TRPV1 activation may trigger AMPK-dependent signaling, which leads to enhanced activation of AMPK and eNOS and retarded development of atherosclerosis.

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Section: Discussionsupporting

confidence: 92%

Section: A M P K I N T R P V 1 -M E D I a T E D E N O S A C T I Vsupporting

confidence: 91%

Section: A M P K I N T R P V 1 -M E D I a T E D E N O S A C T I Vmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

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Implication of AMP-Activated Protein Kinase in Transient Receptor Potential Vanilloid Type 1-Mediated Activation of Endothelial Nitric Oxide Synthase

Ching

Chen

et al. 2012

Mol Med

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“…Activation of eNOS‐NO signaling is suggested to be a major mechanism of clinical therapeutic drugs in treating cardiovascular diseases 26, 27, 28. eNOS can be activated by physiological and metabolic stimuli, such as shear stress and clinical therapeutic drugs, and result in NO production.…”

Section: Discussionmentioning

confidence: 99%

Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

Hsu

Zhao²,

Lin

et al. 2016

JAHA

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BackgroundAsymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase (eNOS), is considered a risk factor for the pathogenesis of cardiovascular diseases. Simvastatin, a lipid‐lowering drug with other pleiotropic effects, has been widely used for treatment of cardiovascular diseases. However, little is known about the effect and underlying molecular mechanisms of ADMA on the effectiveness of simvastatin in the vascular system.Methods and ResultsWe conducted a prospective cohort study to enroll 648 consecutive patients with coronary artery disease for a follow‐up period of 8 years. In patients with plasma ADMA level ≥0.49 μmol/L (a cut‐off value from receiver operating characteristic curve), statin treatment had no significant effect on cardiovascular events. We also conducted randomized, controlled studies using in vitro and in vivo models. In endothelial cells, treatment with ADMA (≥0.5 μmol/L) impaired simvastatin‐induced nitric oxide (NO) production, endothelial NO synthase (eNOS) phosphorylation, and angiogenesis. In parallel, ADMA markedly increased the activity of NADPH oxidase (NOX) and production of reactive oxygen species (ROS). The detrimental effects of ADMA on simvastatin‐induced NO production and angiogenesis were abolished by the antioxidant, N‐acetylcysteine, NOX inhibitor, or apocynin or overexpression of dimethylarginine dimethylaminohydrolase 2 (DDAH‐2). Moreover, in vivo, ADMA administration reduced Matrigel plug angiogenesis in wild‐type mice and decreased simvastatin‐induced eNOS phosphorylation in aortas of apolipoprotein E–deficient mice, but not endothelial DDAH‐2‐overexpressed aortas.ConclusionsWe conclude that ADMA may trigger NOX‐ROS signaling, which leads to restricting the simvastatin‐conferred protection of eNOS activation, NO production, and angiogenesis as well as the clinical outcome of cardiovascular events.

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Transient Receptor Potential Channels and Endothelial Cell Calcium Signaling

Thakore

Earley

2019

Comprehensive Physiology

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The vascular endothelium is a broadly distributed and highly specialized organ. The endothelium has a number of functions including the control of blood vessels diameter through the production and release of potent vasoactive substances or direct electrical communication with underlying smooth muscle cells, regulates the permeability of the vascular barrier, stimulates the formation of new blood vessels, and influences inflammatory and thrombotic processes. Endothelial cells that make up the endothelium express a variety of cell-surface receptors and ion channels on the plasma membrane that are capable of detecting circulating hormones, neurotransmitters, oxygen tension, and shear stress across the vascular wall. Changes in these stimuli activate signaling cascades that initiate an appropriate physiological response. Increases in the global intracellular Ca 2+ concentration and localized Ca 2+ signals that occur within specialized subcellular microdomains are fundamentally important components of many signaling pathways in the endothelium. The transient receptor potential (TRP) channels are a superfamily of cationpermeable ion channels that act as a primary means of increasing cytosolic Ca 2+ in endothelial cells. Consequently, TRP channels are vitally important for the major functions of the endothelium. In this review, we provide an in-depth discussion of Ca 2+-permeable TRP channels in the endothelium and their role in vascular regulation.

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Molecular mechanisms of activation of endothelial nitric oxide synthase mediated by transient receptor potential vanilloid type 1

Abstract: TRPV1 activation in ECs may trigger Ca(2+)-dependent PI3K/Akt/CaMKII signalling, which leads to enhanced phosphorylation of TRPV1, increased TRPV1-eNOS complex formation, eNOS activation and, ultimately, NO production.

Cited by 124 publications

References 35 publications

Implication of AMP-Activated Protein Kinase in Transient Receptor Potential Vanilloid Type 1-Mediated Activation of Endothelial Nitric Oxide Synthase

Implication of AMP-Activated Protein Kinase in Transient Receptor Potential Vanilloid Type 1-Mediated Activation of Endothelial Nitric Oxide Synthase

Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

Transient Receptor Potential Channels and Endothelial Cell Calcium Signaling

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