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      A Genetic Polymorphism in the Pannexin1 Gene Predisposes for The Development of Endothelial Dysfunction with Increasing BMI

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          Abstract

          Endothelial dysfunction worsens when body mass index (BMI) increases. Pannexin1 (Panx1) ATP release channels regulate endothelial function and lipid homeostasis in mice. We investigated whether the Panx1-400A>C single nucleotide polymorphism (SNP), encoding for a gain-of-function channel, associates with endothelial dysfunction in non-obese and obese individuals. Myocardial blood flow (MBF) was measured by 13N-ammonia positron emission/computed tomography at rest, during cold pressor test (CPT) or dipyridamole-induced hyperemia. Myocardial flow reserve (MFR) and endothelial function were compared in 43 non-obese (BMI < 30 kg/m 2) vs. 29 obese (BMI ≥ 30 kg/m 2) participants and genotyping for the Panx1-400A>C SNP was performed. Groups comprised subjects homozygous for the C allele ( n = 40) vs. subjects with at least one A allele ( n = 32). MBF (during CPT or hyperemia), MFR and endothelial function correlated negatively with BMI in the full cohort. BMI correlated negatively with MFR and endothelial function in non-obese Panx1-400C subjects, but not in Panx1-400A individuals nor in obese groups. BMI correlated positively with serum triglycerides, insulin or HOMA. MFR correlated negatively with these factors in non-obese Panx1-400C but not in Panx1-400A individuals. Here, we demonstrated that Panx1-400C SNP predisposes to BMI-dependent endothelial dysfunction in non-obese subjects. This effect may be masked by excessive dysregulation of metabolic factors in obese individuals.

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          Endothelium-dependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interaction.

          This study attempted to assess whether coronary risk factors are associated with endothelial dysfunction in the systemic arteries of asymptomatic men and women. Endothelial dysfunction is present in adults with established atherosclerosis. It is not known whether risk factors interact to produce endothelial dysfunction in clinically well subjects early in the natural history. Using high resolution ultrasound, we measured arterial diameter at rest, after reactive hyperemia (with increased flow causing endothelium-dependent dilation) and after sublingual nitroglycerin (an endothelium-independent dilator). Arterial responses were studied noninvasively in 500 clinically well, nonhypertensive subjects (252 men, 248 women; mean [+/- SD] age 36 +/- 15 years, range 5 to 73), including 179 current and former smokers. The superficial femoral artery was studied in 46 subjects and the brachial artery in 454. Flow-mediated dilation ranged from -1% to +17%. All arteries dilated in response to administration of nitroglycerin (17 +/- 6%), suggesting an abnormality of endothelial function in subjects with impaired flow-mediated dilation. On univariate analysis, reduced flow-mediated dilation was significantly related to hypercholesterolemia, cigarette smoking, higher blood pressure, male gender, older age, family history of premature vascular disease and larger vessel size (p < 0.01). By multiple stepwise regression analysis, reduced flow-mediated dilation was independently associated with cigarette smoking, older age, male gender and larger vessel size (p < 0.005) but not with total cholesterol level, blood pressure or family history. A composite risk factor score was independently related to flow-mediated dilation (r = -0.30, p < 0.0001), suggesting risk factor interaction. Loss of endothelium-dependent dilation in the systemic arteries occurs in the preclinical phase of vascular disease and is associated with interaction of the same risk factors known to predispose to atherosclerosis and its complications in later life.
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            Metabotropic NMDA receptor signaling couples Src family kinases to pannexin-1 during excitotoxicity.

            Overactivation of neuronal N-methyl-D-aspartate receptors (NMDARs) causes excitotoxicity and is necessary for neuronal death. In the classical view, these ligand-gated Ca(2+)-permeable ionotropic receptors require co-agonists and membrane depolarization for activation. We report that NMDARs signal during ligand binding without activation of their ion conduction pore. Pharmacological pore block with MK-801, physiological pore block with Mg(2+) or a Ca(2+)-impermeable NMDAR variant prevented NMDAR currents, but did not block excitotoxic dendritic blebbing and secondary currents induced by exogenous NMDA. NMDARs, Src kinase and Panx1 form a signaling complex, and activation of Panx1 required phosphorylation at Y308. Disruption of this NMDAR-Src-Panx1 signaling complex in vitro or in vivo by administration of an interfering peptide either before or 2 h after ischemia or stroke was neuroprotective. Our observations provide insights into a new signaling modality of NMDARs that has broad-reaching implications for brain physiology and pathology.
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              Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease.

              In animals, acetylcholine dilates normal arteries and produces vasoconstriction in the presence of hypercholesterolemia, hypertension, or atherosclerosis, reflecting endothelial cell dysfunction. In patients with angiographically smooth coronary arteries, acetylcholine has been reported to produce both vasodilation and constriction. To test the hypothesis that the acetylcholine response relates to risk factors for coronary artery disease, acetylcholine 10(-8) to 10(-6) M was infused into the left anterior descending or circumflex coronary artery, and diameter changes were assessed with quantitative angiography in 34 patients with angiographically smooth coronary arteries. The acetylcholine response ranged from +37% (dilation) to -53% (constriction) at the peak acetylcholine dose. All coronary arteries dilated in response to nitroglycerin (26 +/- 17%), suggesting an abnormality of endothelial function in the patients with a constrictor response to acetylcholine. By multiple stepwise regression analysis, serum cholesterol (p less than 0.01), male gender (p less than 0.001), family history (p less than 0.05), age (p less than 0.05), cholesterol level (p less than 0.01), and total number of risk factors (p less than 0.0001) were independently associated with the acetylcholine response. Thus, coronary risk factors are associated with loss of endothelium-dependent vasodilation. The development of vasoconstriction is likely to be an abnormality of endothelial function that precedes atherosclerosis or an early marker of atherosclerosis not detectable by angiography.
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                Author and article information

                Journal
                Biomolecules
                Biomolecules
                biomolecules
                Biomolecules
                MDPI
                2218-273X
                31 January 2020
                February 2020
                : 10
                : 2
                : 208
                Affiliations
                [1 ]Department of Pathology and Immunology, University of Geneva,1211 Geneva, Switzerland; brenda.kwakchanson@ 123456unige.ch (B.R.K.); sandrine.morel@ 123456unige.ch (S.M.)
                [2 ]Department of Medical Specialities-Cardiology, University of Geneva, 1211 Geneva, Switzerland; alessandra.quercioli@ 123456libero.it (A.Q.); fabrizio.montecucco@ 123456unige.it (F.M.); thschindler@ 123456wustl.edu (T.H.S.)
                Author notes
                Author information
                https://orcid.org/0000-0002-0405-5397
                https://orcid.org/0000-0003-0823-8729
                https://orcid.org/0000-0002-2141-7716
                https://orcid.org/0000-0003-0015-0044
                https://orcid.org/0000-0003-1538-3553
                Article
                biomolecules-10-00208
                10.3390/biom10020208
                7072696
                32023876
                61bc0bf7-36df-4895-a040-f0e9e976d3e4
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 12 December 2019
                : 26 January 2020
                Categories
                Article

                panx1,polymorphism,endothelial function,obesity
                panx1, polymorphism, endothelial function, obesity

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