P3111Empagliflozin, a SGLT2 inhibitor, attenuates endothelial dysfunction and atherogenesis by inhibiting inflammatory responses in the vasculature and adipose tissue in diabetic apolipoprotein E-deficient

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
B Ganbaatar ◽  
D Fukuda ◽  
S Yagi ◽  
K Kusunose ◽  
H Yamada ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Apolipoprotein E ◽  
Aortic Arch ◽  
Atherosclerotic Plaque ◽  
Aortic Root ◽  
Untreated Group ◽  
Lipid Deposition ◽  
Underlying Mechanisms ◽  
Inflammatory Molecules

Abstract Background Inflammation and oxidative stress associated with hyperglycemia are major causes of vascular dysfunction and cardiovascular complications in diabetes. Recent studies reported that cardioprotective effects of sodium glucose co-transporter 2 (SGLT2) inhibitors, however underlying mechanisms are still obscure. Purpose The aim of this study was to investigate whether empagliflozin attenuates atherogenesis and endothelial dysfunction in diabetic apolipoprotein E-deficient (ApoE−/−) mice and investigated underlying mechanisms. Methods ApoE−/− mice were injected with streptozotocin (75 mg/kg) for 3 consecutive days. One week after last injection, a western type diet and administration of empagliflozin (20 mg/kg/day) or vehicle via oral gavage were started. Atherosclerotic plaque area was examined by en face Sudan IV staining. Lipid deposition and inflammatory features of atherosclerotic plaques was examined on lesions in the aortic root by immunohistochemical analysis. Vascular function was assessed by isometric tension recording. mRNA or protein expression level was examined by quantitative RT-PCR (qPCR) or western blot analysis, respectively. In in vitro experiments, murine macrophage cell line, RAW264.7, was used. Results Treatment with empagliflozin for 12 weeks significantly decreased atherosclerotic plaque size in the aortic arch compared with untreated group (p<0.01). Empagliflozin reduced blood glucose (p<0.001) and plasma lipid levels. Results of histological analyses revealed that empagliflozin decreased lipid deposition, macrophage accumulation, and the expression of inflammatory molecules in the aortic root. Empagliflozin treatment for 8 weeks significantly attenuated endothelial dysfunction as determined by vascular response to acetylcholine. qPCR results demonstrated that empagliflozin reduced the expression of inflammatory molecules such as MCP-1 (p<0.05), ICAM-1 (p<0.05) and Nox-2 (p<0.05), a major NADPH oxidase subunit, in the aorta compared with the untreated group. Furthermore, empagliflozin significantly mitigated the expression of these inflammatory molecules in fat tissues around the aortic arch as determined by qPCR. In in vitro studies, methylglyoxal (MGO), a precursor of AGEs, increased the expression of inflammatory molecules (e.g., MCP-1, IL-1b and TNF-a (p<0.05, respectively)) in RAW264.7 cells. MGO also significantly induced activation of JNK and p38 MAP kinase (p<0.001, respectively) in this cell-type. Conclusions Empagliflozin attenuated endothelial dysfunction and atherogenesis in diabetic ApoE−/− mice. Reduction of inflammation in the vasculature and peri-vascular adipose tissues may have a role as underlying mechanisms at least partially.

P722Glycemic control with canagliflozin, a SGLT-2 inhibitor, attenuates atherosclerosis and endothelial dysfunction in diabetic apolipoprotein e-deficient mice

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Rahadian ◽  
D Fukuda ◽  
H Salim ◽  
S Yagi ◽  
K Kusunose ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Apolipoprotein E ◽  
Umbilical Vein ◽  
Total Cholesterol Level ◽  
Vascular Endothelial Cell ◽  
Atherosclerotic Lesion ◽  
Umbilical Vein Endothelial Cells ◽  
Inflammatory Molecules

Abstract Background Canagliflozin is a SGLT-2 inhibitor, a novel type of drug for type 2 diabetes mellitus treatment. Recent studies have shown that SGLT-2 inhibitors reduce cardiovascular events, although the mechanism is still unknown. Purpose The aim of our study was to examine the effect of canagliflozin on vascular endothelial cell. Method Eight-week-old apolipoprotein E-deficient (ApoE−/−) mice were treated with streptozotocin (STZ, 75 mg/kg/day) in three consecutive days by intraperitoneal injection to induce diabetes. Diabetic ApoE−/− mice were treated with canagliflozin (30 mg/kg/day) by gavage for 12 weeks or 8 weeks to examine its effect on atherosclerosis or endothelial function, respectively. Results Canagliflozin significantly decreased blood glucose level (P<0.001), triglyceride level (P<0.05), and total cholesterol level (P<0.05). Sudan IV staining on the aortic arch showed that canagliflozin decreased atherosclerotic lesion progression (P<0.05). Histological analyses using atherosclerotic lesions in the aortic root showed that canagliflozin reduced lipid disposition (P<0.01), macrophage accumulation (P<0.001, and expression of adhesion molecules such as ICAM-1, and VCAM-1 (P<0.01, and P<0.05 respectively). Canagliflozin also attenuated the development of endothelial dysfunction as determined by acetylcholine-dependent vasodilation (P<0.05), and reduced the expression of inflammatory molecules, such as ICAM-1 and VCAM-1 (P<0.01), also MCP-1, F4/80, IL6, and iNOS (P<0.05) in the aorta. Canagliflozin reduced oxidative stress as determined by the reduction of the expression of NOX2, NOX4, p22phox, p47phox in the aorta and by the urinary excretion of 8-OHdG. In in vitro experiment using human umbilical vein endothelial cells (HUVEC), methylglyoxal (MGO), a precursor of advanced glycation end products, significantly increased the expression of inflammatory molecules such as ICAM-1, MCP-1, and p22phox in (P<0.05, respectively). MGO also decreased the phosphorylation of eNOSser1177 and Akt, and increased phosphorylation of P38 MAPK in HUVEC. Conclusion Glucose lowering effect by canagliflozin attenuates the development of endothelial dysfunction and atherogenesis in diabetic ApoE−/− mice. Anti-inflammatory effect due to the reduction of glucose toxicity on endothelial cells might be one of the mechanisms.

scholarly journals Comparison of Selenium Nanoparticles and Sodium Selenite on the Alleviation of Early Atherosclerosis by Inhibiting Endothelial Dysfunction and Inflammation in Apolipoprotein E-Deficient Mice

2021 ◽  
Vol 22 (21) ◽  
pp. 11612
Author(s):  
Junying Xiao ◽  
Na Li ◽  
Shengze Xiao ◽  
Yuzhou Wu ◽  
Hongmei Liu
Keyword(s):  
Endothelial Dysfunction ◽  
Apolipoprotein E ◽  
Animal Studies ◽  
Vascular Inflammation ◽  
Selenium Nanoparticles ◽  
In Vivo Experiments ◽  
Nitric Oxide Level ◽  
Underlying Mechanisms ◽  
Atherosclerosis Prevention

Atherosclerosis and related cardiovascular diseases represent the greatest threats to human health, worldwide. Previous animal studies showed that selenium nanoparticles (SeNPs) and Na2SeO3 might have anti-atherosclerotic activity, but the underlying mechanisms are poorly elucidated. This study compared the anti-atherosclerotic activity of SeNPs stabilized with chitosan (CS-SeNPs) and Na2SeO3 and the related mechanism in a high-fat-diet-fed apolipoprotein E-deficient mouse model of atherosclerosis. The results showed that oral administration of both CS-SeNPs and Na2SeO3 (40 μg Se/kg/day) for 10 weeks significantly reduced atherosclerotic lesions in mouse aortae. Mechanistically, CS-SeNPs and Na2SeO3 not only alleviated vascular endothelial dysfunction, as evidenced by the increase of serum nitric oxide level and the decrease of aortic adhesion molecule expression, but also vascular inflammation, as evidenced by the decrease of macrophage recruitment as well as the expression of proinflammatory molecules. Importantly, these results were replicated within in-vivo experiments on the cultured human endothelial cell line EA.hy926. Overall, CS-SeNPs had a comparable effect with Na2SeO3 but might have more potential in atherosclerosis prevention due to its lower toxicity. Together, these results provide more insights into the mechanisms of selenium against atherosclerosis and further highlight the potential of selenium supplementation as a therapeutic strategy for atherosclerosis.

Abstract 13405: Genetic Deletion of Stimulator of Interferon Genes Attenuates Atherogenesis in Apolipoprotein E-deficient Mice

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Phuong T Pham ◽  
Daiju Fukuda ◽  
Masataka Sata
Keyword(s):  
Innate Immunity ◽  
Apolipoprotein E ◽  
Aortic Arch ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Vascular Inflammation ◽  
Atherosclerotic Plaques ◽  
Atherosclerotic Lesions ◽  
Gene And Protein Expression ◽  
Inflammatory Molecules

Introduction: Recent studies show the contribution of innate immunity system to the pathogenesis of inflammatory diseases, including atherosclerosis. Stimulation of interferon genes (STING), originally known as a cytosolic DNA sensor, recognizes cytosolic DNA fragments, activating innate immunity. Here, we investigated whether STING contributes to the development of vascular inflammation and atherogenesis in apolipoprotein E-deficient (Apoe –/– ) mice. Methods and Results: The expression of STING increased in the atherosclerotic aorta in both gene and protein expression levels. STING-deficient Apoe –/– (STING –/– Apoe –/– ) mice reduced atherosclerotic lesions in the aortic arch ( P <0.05), along with the reduction of lipid and macrophage accumulation in atherosclerotic plaques ( P <0.05, respectively), and inflammatory molecule expression in the aorta compared with those in Apoe –/– mice after 20 weeks on a western-type diet. Also, pharmacologic blockade of STING in Apoe –/– mice for 12 weeks treatment attenuated atherogenesis in the aortic arch ( P <0.05), reduced the accumulation of lipid in atherosclerotic plaques ( P <0.05) with no alteration of metabolic parameters. Restoration of STING in bone marrow in STING –/– Apoe –/– mice promoted atherogenesis ( P <0.05), lipid deposition ( P <0.05), and vascular inflammation. cGAMP, a specific STING agonist, or mitochondrial DNA extracted from macrophages promoted expression of inflammatory molecules more effectively in Apoe -/- macrophages than in STING –/– Apoe –/– macrophages, while C-176, a specific STING inhibitor, attenuated these inflammatory responses. The results of western blotting showed the involvement of NF-κB and IRF-3 signaling in STING-associated vascular inflammation and macrophage activation. Furthermore, in humans, STING expression was confirmed in atherosclerotic lesions in the carotid artery. Conclusion: STING signaling activates macrophages, promotes vascular inflammation and atherosclerosis in Apoe -/- mice. Our results suggest that STING may serve as a potential therapeutic target for atherosclerosis.

Modulation of the effects of chylomicron remnants on endothelial function by minor dietary lipid components

2007 ◽  
Vol 35 (3) ◽  
pp. 446-450 ◽  
Author(s):  
J.S. Perona ◽  
R. Cabello-Moruno ◽  
V. Ruiz-Gutierrez
Keyword(s):  
Endothelial Dysfunction ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Dietary Lipid ◽  
Dietary Lipids ◽  
Atherosclerotic Process ◽  
Chylomicron Remnants ◽  
Inflammatory Molecules ◽  
Lipid Components

There is emerging evidence that minor components from dietary oils can modulate or even improve events occurring in the development of atherosclerosis. One of the earliest events of the atherosclerotic process is endothelial dysfunction, which is an activation of the endothelium manifested by an increase in pro-inflammatory molecules, such as cytokines and adhesion molecules. Chylomicron remnants, such as LDL (low-density lipoprotein), are considered to be pro-atherogenic lipoproteins because they interact with endothelial cells and macrophages, increasing endothelial dysfunction mainly by the disturbance of the redox state in the cell. However, chylomicrons are, at the same time, the natural carriers of dietary lipids in plasma, which gives minor lipid components the opportunity to interact with the cells implicated in endothelial dysfunction and atherogenesis. Some of these components are known to exhibit antioxidant, anti-inflammatory and anti-atherogenic effects in vitro, even forming part of triacylglycerol-rich lipoproteins, such as chylomicrons.

scholarly journals Leucine decreases intramyocellular lipid deposition in an mTORC1-independent manner in palmitate-treated C2C12 myotubes

2020 ◽  
Vol 318 (2) ◽  
pp. E152-E163
Author(s):  
Hexirui Wu ◽  
Sami Dridi ◽  
Yan Huang ◽  
Jamie I. Baum
Keyword(s):  
Fatty Acid ◽  
Plasma Concentration ◽  
Mitochondrial Biogenesis ◽  
Mammalian Target Of Rapamycin ◽  
C2c12 Myotubes ◽  
Lipid Deposition ◽  
Intramyocellular Lipid ◽  
Independent Manner ◽  
Underlying Mechanisms

Higher intramyocellular lipid (IMCL) deposition in skeletal muscle is commonly observed in patients with obesity, resulting in mitochondrial damage. Palmitic acid, a saturated fatty acid, has been reported to induce obesogenic conditions in C2C12 myotubes. Leucine has been shown to improve obesity-related metabolic signatures; however, evidence for the effect of leucine on IMCL and the underlying mechanisms are still lacking. The objective of this study was to determine the effect of leucine on IMCL deposition and identify the potential mechanisms. Palmitate-treated C2C12 myotubes were used as an in vitro model of obesity. Two doses of leucine were used: 0.5 mM (postprandial physiological plasma concentration) and 1.5 mM (supraphysiological plasma concentration). Rapamycin was used to determine the role of mammalian target of rapamycin complex 1 (mTORC1) in leucine’s regulation of lipid deposition in C2C12 myotubes. One-way ANOVA followed by Tukey’s post hoc test was used to calculate differences between treatment groups. Our results demonstrate that leucine reduces IMCL deposition in an mTORC1-independent fashion. Furthermore, leucine acts independently of mTORC1 to upregulate gene expression related to fatty acid metabolism and works through both mTORC1-dependent and mTORC1-independent pathways to regulate mitochondrial biogenesis in palmitate-treated C2C12 myotubes. In agreement with increased mitochondrial biogenesis, increased mitochondrial content, circularity, and decreased autophagy are observed in the presence of 1.5 mM leucine. Taken together, the results indicate leucine reduces IMCL potentially through an mTORC1-independent pathway in palmitate-treated C2C12 myotubes.

scholarly journals Angiotensin II Induces Oxidative Stress and Endothelial Dysfunction in Mouse Ophthalmic Arteries via Involvement of AT1 Receptors and NOX2

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1238
Author(s):  
Michael Birk ◽  
Ewa Baum ◽  
Jenia Kouchek Zadeh ◽  
Caroline Manicam ◽  
Norbert Pfeiffer ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Point Of View ◽  
Ang Ii ◽  
Ocular Diseases ◽  
Underlying Mechanisms ◽  
Ophthalmic Arteries

Angiotensin II (Ang II) has been implicated in the pathophysiology of various age-dependent ocular diseases. The purpose of this study was to test the hypothesis that Ang II induces endothelial dysfunction in mouse ophthalmic arteries and to identify the underlying mechanisms. Ophthalmic arteries were exposed to Ang II in vivo and in vitro to determine vascular function by video microscopy. Moreover, the formation of reactive oxygen species (ROS) was quantified and the expression of prooxidant redox genes and proteins was determined. The endothelium-dependent artery responses were blunted after both in vivo and in vitro exposure to Ang II. The Ang II type 1 receptor (AT1R) blocker, candesartan, and the ROS scavenger, Tiron, prevented Ang II-induced endothelial dysfunction. ROS levels and NOX2 expression were increased following Ang II incubation. Remarkably, Ang II failed to induce endothelial dysfunction in ophthalmic arteries from NOX2-deficient mice. Following Ang II incubation, endothelium-dependent vasodilation was mainly mediated by cytochrome P450 oxygenase (CYP450) metabolites, while the contribution of nitric oxide synthase (NOS) and 12/15-lipoxygenase (12/15-LOX) pathways became negligible. These findings provide evidence that Ang II induces endothelial dysfunction in mouse ophthalmic arteries via AT1R activation and NOX2-dependent ROS formation. From a clinical point of view, the blockade of AT1R signaling and/or NOX2 may be helpful to retain or restore endothelial function in ocular blood vessels in certain ocular diseases.

Effects of the Tibetan herbal preparation PADMA 28 on blood lipids and lipid oxidisability in subjects with mild hypercholesterolaemia

VASA ◽  
2005 ◽  
Vol 34 (1) ◽  
pp. 11-17 ◽  
Author(s):  
Brunner-La Rocca ◽  
Schindler ◽  
Schlumpf ◽  
Saller ◽  
Suter
Keyword(s):  
Endothelial Dysfunction ◽  
Blood Lipids ◽  
Ex Vivo ◽  
Hdl Cholesterol ◽  
Blood Lipid ◽  
Tibetan Medicine ◽  
Double Blind ◽  
Intraarterial Infusion ◽  
Padma 28

Background: Previous studies showed an anti-atherosclerotic effect of PADMA 28, an herbal formula based on Tibetan medicine. As the mechanisms of action are not fully understood, we investigated whether PADMA 28 may lower blood lipids and lipid oxidisability, and affect early endothelial dysfunction. Patients and methods: Sixty otherwise healthy subjects with total cholesterol ≥5.2 mmol/l and < 8.0 mmol/l were randomly assigned to placebo or PADMA 28, 3 x 2 capsules daily, for 4 weeks (double-blind). Blood lipids (total, LDL-, and HDL-cholesterol, triglycerides, Apo-lipoprotein A1 and B) and ex vivo lipid oxidisability were measured before and after treatment. In a subset of 24 subjects, endothelial function was assessed using venous occlusion plethysmography with intraarterial infusion of acetylcholine. Isolated LDL and plasma both untreated and pre-treated with PADMA 28 extract were oxidised by the radical generator AAPH. Conjugated diene formation was measured at 245 nm. Results: Blood lipids did not change during the study in both groups. In contrast to previous reports in mild hypercholesterolaemia, no endothelial dysfunction was seen and, consequently, was not influenced by therapy. Ex vivo blood lipid oxidisability was significantly reduced with PADMA 28 (area under curve: 5.29 ± 1.62 to 4.99 ± 1.46, p = 0.01), and remained unchanged in the placebo group (5.33 ± 1.88 to 5.18 ± 1.78, p > 0.1). This effect persisted one week after cessation of medication. In vitro experiments confirmed the prevention of lipid peroxidation in the presence of PADMA 28 extracts. Persistent protection was also seen for LDL isolated from PADMA 28-pretreated blood after being subjected to rigorous purification. Conclusions: This study suggests that the inhibition of blood lipid oxidisability by PADMA 28 may play a role in its anti-atherosclerotic effect.

Dilatation of the entire thoracic aorta in patients with bicuspid aortic valve: a magnetic resonance angiography study

VASA ◽  
2005 ◽  
Vol 34 (3) ◽  
pp. 181-185 ◽  
Author(s):  
Westhoff-Bleck ◽  
Meyer ◽  
Lotz ◽  
Tutarel ◽  
Weiss ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Magnetic Resonance Angiography ◽  
Aortic Valve ◽  
Pulmonary Artery ◽  
Aortic Arch ◽  
Thoracic Aorta ◽  
Aortic Root ◽  
Ascending Aorta ◽  
Descending Aorta ◽  
Severe Aortic Regurgitation

Background: The presence of a bicuspid aortic valve (BAV) might be associated with a progressive dilatation of the aortic root and ascending aorta. However, involvement of the aortic arch and descending aorta has not yet been elucidated. Patients and methods: Magnetic resonance angiography (MRA) was used to assess the diameter of the ascending aorta, aortic arch, and descending aorta in 28 patients with bicuspid aortic valves (mean age 30 ± 9 years). Results: Patients with BAV, but without significant aortic stenosis or regurgitation (n = 10, mean age 27 ± 8 years, n.s. versus control) were compared with controls (n = 13, mean age 33 ± 10 years). In the BAV-patients, aortic root diameter was 35.1 ± 4.9 mm versus 28.9 ± 4.8 mm in the control group (p < 0.01). The diameter of the ascending aorta was also significantly increased at the level of the pulmonary artery (35.5 ± 5.6 mm versus 27.0 ± 4.8 mm, p < 0.001). BAV-patients with moderate or severe aortic regurgitation (n = 18, mean age 32 ± 9 years, n.s. versus control) had a significant dilatation of the aortic root, ascending aorta at the level of the pulmonary artery (41.7 ± 4.8 mm versus 27.0 ± 4.8 mm in control patients, p < 0.001) and, furthermore, significantly increased diameters of the aortic arch (27.1 ± 5.6 mm versus 21.5 ± 1.8 mm, p < 0.01) and descending aorta (21.8 ± 5.6 mm versus 17.0 ± 5.6 mm, p < 0.01). Conclusions: The whole thoracic aorta is abnormally dilated in patients with BAV, particularly in patients with moderate/severe aortic regurgitation. The maximum dilatation occurs in the ascending aorta at the level of the pulmonary artery. Thus, we suggest evaluation of the entire thoracic aorta in patients with BAV.

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