The Good Neighbor

Yar, Sumeyye; Chang, Hsiang Chun; Ardehali, Hossein

doi:10.1161/circresaha.116.308338

Cited by 7 publications

(2 citation statements)

References 20 publications

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“…Other miRNAs, such as miR-126, have been shown to preserve normal endothelial function, likely via blocking unwanted endothelial activation ( 67 ). These findings highlight the role of adipose ECs in the development of obesity-induced insulin resistance and the potential of using miRNAs as a tool to modulate EC function ( 68 ).…”

Section: Endothelial Regulation Of Obesity-associated Insulin Resistamentioning

confidence: 83%

Vascular Endothelial Regulation of Obesity-Associated Insulin Resistance

Qian

2017

Front. Cardiovasc. Med.

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Obesity is a worldwide epidemic that predisposes individuals to metabolic complications, such as type 2 diabetes mellitus and non-alcoholic fatty liver disease, all of which are related to an imbalance between food intake and energy expenditure. Identification of the pathogenic molecular mechanisms and effective therapeutic approaches are urgently needed. A well-accepted paradigm is that crosstalk between organs/tissues contributes to diseases. Endothelial dysfunction characterizes metabolic disorders and the related vascular complications. Over the past two decades, overwhelming studies have focused on mechanisms that lead to endothelial dysfunction. New investigations, however, have begun to appreciate the opposite direction of the crosstalk: endothelial regulation of metabolism, although the underlying mechanisms remain to be elucidated. This review summarizes the evidence that supports the concept of endothelial regulation of obesity and the associated insulin resistance in fat, liver, and skeletal muscles, the classic targets of insulin. Outstanding questions and future research directions are highlighted. Identification of the mechanisms of vascular endothelial regulation of metabolism may offer strategies for prevention and treatment of obesity and the related metabolic complications.

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Section: Endothelial Regulation Of Obesity-associated Insulin Resistamentioning

confidence: 83%

Vascular Endothelial Regulation of Obesity-Associated Insulin Resistance

Qian

2017

Front. Cardiovasc. Med.

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“…15,126 In addition, eNOS dysfunction can be exacerbated by many genetic manipulations that include (1) deletion of bone morphogenetic protein type II receptors [receptors that activate PKA to cause eNOS phosphorylation at Ser1177; their mutation is associated with the development of pulmonary arterial hypertension]; (2) deletion of α-calcitonin gene-related peptide [neuropeptide that induces the expression of eNOS and causes its phosphorylation by activating PKA and AMPK]; (3) deletion of small GTPase Ras-related protein 1 134 impairing activation of integrins (eg, by shear stress) and the subsequent stimulation of the focal adhesion kinase/PI3K/Akt pathway; (4) endothelium-specific deletion of liver kinase B1 impairing AMPK activation; (5) reduction in the level of S100A1, enhancing PKC activity with increased eNOS phosphorylation at Thr495 and reducing that of the PI3K/Akt and the ERK1/2 pathways with decreased eNOS phosphorylation at Ser1177; and (6) expression of myristoylation-deficient eNOS preventing the membrane targeting and thiopalmitoylation of the enzyme ( Figure 6). 15,51 Experimentally, the occurrence of dysfunction of the NO pathway can be prevented/alleviated by (1) elevation of the circulating levels of adiponectin; (2) activation of angiotensin-converting enzyme 2 or administration of angiotensin [1][2][3][4][5][6][7] ; (3) stimulation of the production or long-term administration of erythropoietin 112 enhancing the activation of Akt; (4) administration of stable melanocortin analogs, cannabidiol, 135 and dietary capsaicin, which activate TRPV1 channels of the endothelial cell membrane leading to calcium influx and calcium-dependent stimulation of calcium/calmodulin-dependent PK II phosphorylating eNOS at Ser1177; (5) administration of AMPK-activators such as AICAR; and (6) upregulation of micro-RNA-181b 136 (present in endothelial cells of adipose tissue after high-fat diet; which suppresses the expression of the leucine-rich repeat PP-2 that dephosphorylates and inactivates Akt). 15 In addition, the following molecular maneuvers improve endothelium-dependent, NO-mediated responses: (1) overexpression of SR-transmembrane protein stromal interaction molecule 1, which increases capacitive calcium entry; (2) deletion of caveolin-1 thereby facilitating calcium-calmodulin binding to eNOS; (3) activation of NAD(P)H:quinone oxidoreductase with increased production of cyclic ADP ribose; (4) deletion, reduction, or inhibition of TLR2 and TLR4 reducing the activation of the NFκB pathway; (5) Krüppel-like factor-2 gene therapy increasing eNOS gene transcription; (6) knockin of eNOS with a single amino acid mutation replacing serine by aspartate at the Ser1176 phosphorylation site (the murine site corresponding to Ser1177 in humans) to produce a phosphomimetic hyperactive form of eNOS; (7) h...…”

Section: Reduced Protein Dimerizationmentioning

confidence: 99%

Thirty Years of Saying NO

Vanhoutte

Zhao

et al. 2016

Circulation Research

330

156

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T he historical demonstration by Furchgott and Zawadzki 1 that removal of the endothelium abrogates the in vitro vasodilator effect of acetylcholine has led to the identification 30 years ago of nitric oxide (NO) as a major endogenous local regulator of vascular tone. [2][3][4][5][6][7][8][9][10] When the ability of endothelial cells to produce NO is blunted, the ensuing vascular dysfunction sets the stage for the occurrence of cardiovascular disease in general, and atherosclerosis in particular. [11][12][13][14][15] This review focuses, stepby-step, on the bioavailability (production, action, and disposition) of endothelium-derived NO as local regulator of vascular tone in health and disease. Obviously, there is much more than NO in the control of the degree of contraction of underlying vascular smooth muscle cells exerted by the endothelial cells. Indeed, they generate also prostacyclin and hyperpolarizing signals (initiating endothelium-dependent hyperpolarization [EDH] and thus relaxation) and produce vasoconstrictor mediators (endothelium-derived contracting factors and the peptide endothelin-1); those have been discussed elsewhere in detail. 15-22 Endothelial Sources of NO NO SynthaseThree NO synthase (NOS) isozymes, which are encoded by different genes, catalyze the production of NO from l-arginine: neuronal NOS (or NOS-1), cytokine-inducible NOS (iNOS or NOS-2), and endothelial NOS (eNOS or NOS-3).6,23-25 Although iNOS can be induced (by lipopolysaccharides and inflammatory cytokines) and neuronal NOS can be present in the blood vessel

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The future of pleiotropic therapy in heart failure. Lessons from the benefits of exercise training on endothelial function

Keulenaer

Segers

Zannad

et al. 2017

European J of Heart Fail

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A novel generation of drugs is introduced in the treatment of heart failure (HF). These drugs, including phosphodiesterase-5 inhibitors, guanylate cyclase stimulators and activators, share the feature that their action is either endothelial-mediated or substitutes for endothelial pathways, in particular the nitric oxide-cyclic guanosine monophosphate pathway, thereby influencing homeostatic balances in virtually each organ system in a pleiotropic fashion. Unfortunately, recent clinical trials with some of these drugs have shown disappointing results, at least in the setting of HF with a preserved ejection fraction. This suggests that their clinical use may require approaches that diverge from traditional pharmacological approaches, the latter often titrated on the effects of drugs on haemodynamic parameters or single biomarkers. In this paper we preconize that HF drugs with an endothelial profile should be applied conform to principles of endothelial physiology and systems pharmacology. This type of drug therapy should be viewed as a systems physio-pharmacological intervention and its clinical use accustomed to systems pharmacological principles, comparable to the systemic endothelial-mediated benefits induced by exercise training in HF. We will review the actions of these drugs and define criteria to which trials with these drugs should comply in order to increase chances of success.

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The Good Neighbor

Cited by 7 publications

References 20 publications

Vascular Endothelial Regulation of Obesity-Associated Insulin Resistance

Vascular Endothelial Regulation of Obesity-Associated Insulin Resistance

Thirty Years of Saying NO

The future of pleiotropic therapy in heart failure. Lessons from the benefits of exercise training on endothelial function

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