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

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.

Download Full-text

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

European Heart Journal ◽

10.1093/eurheartj/ehz745.0186 ◽

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.

Download Full-text

Interleukin-10 inhibits the in vivo and in vitro adverse effects of TNF-α on the endothelium of murine aorta

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00763.2009 ◽

2010 ◽

Vol 299 (4) ◽

pp. H1160-H1167 ◽

Cited By ~ 36

Author(s):

Saiprasad M. Zemse ◽

Chin Wei Chiao ◽

Rob H. P. Hilgers ◽

R. Clinton Webb

Keyword(s):

Endothelial Dysfunction ◽

Interleukin 10 ◽

Enos Expression ◽

Response Curves ◽

Female Mice ◽

In Vivo Experiments ◽

Tnf Α ◽

Significant Impairment

TNF-α is a proinflammatory cytokine and is an important mediator of maternal endothelial dysfunction leading to preeclampsia. In this study, we tested whether IL-10 protects against TNF-α-induced endothelial dysfunction in murine aorta. In in vitro experiments, aortic rings of C57BL/6 female mice were incubated in Dulbecco's modified Eagle's medium in the presence of either vehicle (distilled H2O), TNF-α (4 nmol/l), or recombinant mouse IL-10 (300 ng/ml) or in the presence of both TNF-α and IL-10 for 22 h at 37°C. In in vivo experiments C57BL6/IL-10 knockout female mice were treated with saline or TNF-α (220 ng·kg−1·day−1) for 14 days. Aortic rings were isolated from in vitro and in vivo experiments and mounted in a wire myograph (Danish Myotech) and stretched to a tension of 5 mN. Endothelium-dependent relaxation was assessed by constructing cumulative concentration-response curves to acetylcholine (ACh, 0.001–10 μmol/l) during phenylephrine (10 μmol/l)-induced contraction. As a result, overnight exposure of aortic rings to TNF-α resulted in significant blunted maximal relaxing responses ( Emax) to ACh compared with untreated rings (22 ± 4 vs. 82 ± 3%, respectively). IL-10 knockout mice treated with TNF-α showed significant impairment in ACh responses ( Emax) compared with C57BL/6 mice treated with TNF-α (51 ± 3 vs. 72 ± 3%, respectively). Western blot analysis showed that endothelial nitric oxide synthase (eNOS) expression was reduced by TNF-α in in vitro and in vivo experiments, whereas IL-10 restored the eNOS expression. In conclusion, the anti-inflammatory cytokine IL-10 prevents impairment in endothelium-dependent vasorelaxation caused by TNF-α by protecting eNOS expression.

Download Full-text

Elevated Expression of lncRNA MEG3 Induces Endothelial Dysfunction on HUVECs of IVF Born Offspring via Epigenetic Regulation

10.21203/rs.3.rs-69983/v1 ◽

2020 ◽

Author(s):

Ying Jiang ◽

Hong Zhu ◽

Hong Chen ◽

Meng-Meng Yang ◽

Yi-Chen Yu ◽

...

Keyword(s):

Endothelial Dysfunction ◽

Umbilical Vein ◽

Methylation Status ◽

Vitro Fertilization ◽

In Vivo Experiments ◽

Elevated Expression ◽

Nitrite Nitrate ◽

Umbilical Vein Endothelial Cells

Abstract Background: The cardiovascular dysfunction in children born after in vitro fertilization (IVF) has been of great concern, in our study, we aim to explore potential molecular mechanism for such long-term outcomes. Methods：Real-time qPCR was used to test long non-coding RNA MEG3 and endothelium-derived factors, endothelial nitric oxide synthase (eNOS), endothelin-1(ET1), vascular endothelial growth factor (VEGF). Primary HUVEC after caesarean section was treated with different estradiol concentrations in vitro. Besides, knockdown of MEG3 on HUVEC provided further evidence between MEG3 expression and alteration of NO, ET1, VEGF. Then, by using pyrosequencing, we detected MEG3 promoter methylation status.Results: We found that the expression level of MEG3 was higher in human umbilical vein endothelial cells (HUVECs) of IVF offspring than that in spontaneously born offspring. Furthermore, we found decreased expression of eNOS, VEGF, elevated expression of ET1 in HUVECs from IVF offspring compared to spontaneously born offspring. We further confirmed the results from in-vivo experiments by demonstrating that high-estradiol intrauterine environments lead to abnormal expression of MEG3 and endothelium-derived factors. Meanwhile, silencing MEG3 expression decreased ET1 expression, and increased nitrite, nitrate, VEGF secretion, which could correct the effect we observed in-vivo. With pyrosequencing technology, we found that elevated expression of MEG3 in IVF offspring derived HUVECs was the result of hypomethylation of the MEG3 promoter. Conclusions: Our results demonstrated that higher expression of MEG3 in IVF-born HUVECs, accompanied by lower secretion of eNOS, VEGF, and higher secretion of ET1, which is closely related with endothelial dysfunction, which together provide a potential mechanism addressing high-risk of hypertension in IVF offspring.

Download Full-text

Abnormal endothelial vasomotor and secretory function

10.1093/med/9780199592548.003.0113 ◽

2015 ◽

Author(s):

Thimoteus Speer ◽

Danilo Fliser

Keyword(s):

Endothelial Dysfunction ◽

Endothelial Function ◽

Vascular Inflammation ◽

Secretory Function ◽

Vascular Integrity ◽

Non Invasive ◽

Other Substances ◽

Modified Lipoproteins ◽

And Function

The endothelium plays a crucial role in the maintenance of vascular integrity and function. Nitric oxide produced by endothelial cells is a key player, inducing relaxation of vascular smooth muscle cells, inhibition of vascular inflammation, and prevention of coagulatory activation. Chronic kidney disease (CKD) is characterized by deterioration of different protective endothelial properties, collectively described as endothelial dysfunction. Several factors such as methylarginines, modified lipoproteins, and other substances that accumulate may be involved in the pathogenesis of endothelial dysfunction of CKD. Endothelial dysfunction is suggested to be the first critical step in the initiation of atherosclerosis. Clinical assessment of endothelial function may become important in recognition of patients with increased cardiovascular risk. Beside several invasive and non-invasive methods to assess endothelial function in vivo, measurement of circulating (bio)markers may be useful for the evaluation of endothelial dysfunction.

Download Full-text

Effects and Mechanisms of Tea Regulating Blood Pressure: Evidences and Promises

Nutrients ◽

10.3390/nu11051115 ◽

2019 ◽

Vol 11 (5) ◽

pp. 1115 ◽

Cited By ~ 10

Author(s):

Daxiang Li ◽

Ruru Wang ◽

Jinbao Huang ◽

Qingshuang Cai ◽

Chung S. Yang ◽

...

Keyword(s):

Cardiovascular Diseases ◽

Animal Studies ◽

Large Scale ◽

Molecular Mechanisms ◽

Ex Vivo ◽

Vascular Inflammation ◽

Optimal Dose ◽

Smooth Muscle Contraction ◽

Beneficial Effects ◽

Underlying Mechanisms

Cardiovascular diseases have overtaken cancers as the number one cause of death. Hypertension is the most dangerous factor linked to deaths caused by cardiovascular diseases. Many researchers have reported that tea has anti-hypertensive effects in animals and humans. The aim of this review is to update the information on the anti-hypertensive effects of tea in human interventions and animal studies, and to summarize the underlying mechanisms, based on ex-vivo tissue and cell culture data. During recent years, an increasing number of human population studies have confirmed the beneficial effects of tea on hypertension. However, the optimal dose has not yet been established owing to differences in the extent of hypertension, and complicated social and genetic backgrounds of populations. Therefore, further large-scale investigations with longer terms of observation and tighter controls are needed to define optimal doses in subjects with varying degrees of hypertensive risk factors, and to determine differences in beneficial effects amongst diverse populations. Moreover, data from laboratory studies have shown that tea and its secondary metabolites have important roles in relaxing smooth muscle contraction, enhancing endothelial nitric oxide synthase activity, reducing vascular inflammation, inhibiting rennin activity, and anti-vascular oxidative stress. However, the exact molecular mechanisms of these activities remain to be elucidated.

Download Full-text

The antiatherogenic function of kallistatin and its potential mechanism

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmaa035 ◽

2020 ◽

Vol 52 (6) ◽

pp. 583-589 ◽

Cited By ~ 1

Author(s):

Gang Wang ◽

Jin Zou ◽

Xiaohua Yu ◽

Shanhui Yin ◽

Chaoke Tang

Keyword(s):

Vascular Inflammation ◽

Serine Proteinase ◽

Inverse Correlation ◽

Potential Mechanism ◽

In Vivo Experiments ◽

Promising Therapeutic Target ◽

Artery Disease ◽

Lipoprotein Receptor Related Protein

Abstract Atherosclerosis is the pathological basis of most cardiovascular diseases, the leading cause of morbidity and mortality worldwide. Kallistatin, originally discovered in human serum, is a tissue-kallikrein-binding protein and a unique serine proteinase inhibitor. Upon binding to its receptor integrin β3, lipoprotein receptor-related protein 6, nucleolin, or Krüppel-like factor 4, kallistatin can modulate various signaling pathways and affect multiple biological processes, including angiogenesis, inflammatory response, oxidative stress, and tumor growth. Circulating kallistatin levels are significantly decreased in patients with coronary artery disease and show an inverse correlation with its severity. Importantly, both in vitro and in vivo experiments have demonstrated that kallistatin reduces atherosclerosis by inhibiting vascular inflammation, antagonizing endothelial dysfunction, and improving lipid metabolism. Thus, kallistatin may be a novel biomarker and a promising therapeutic target for atherosclerosis-related diseases. In this review, we focus on the antiatherogenic function of kallistatin and its potential mechanism.

Download Full-text

Isotalatizidine, a C19-diterpenoid alkaloid, attenuates chronic neuropathic pain through stimulating ERK/CREB signaling pathway-mediated microglial dynorphin A expression

Journal of Neuroinflammation ◽

10.1186/s12974-019-1696-9 ◽

2020 ◽

Vol 17 (1) ◽

Cited By ~ 6

Author(s):

Shuai Shao ◽

Huan Xia ◽

Min Hu ◽

Chengjuan Chen ◽

Junmin Fu ◽

...

Keyword(s):

Neuropathic Pain ◽

Lateral Roots ◽

Intrathecal Injection ◽

Dependent Manner ◽

Dynorphin A ◽

Diterpenoid Alkaloid ◽

P38 Inhibitor ◽

In Vivo Experiments ◽

Underlying Mechanisms

Abstract Background Isotalatizidine is a representative C19-diterpenoid alkaloid extracted from the lateral roots of Aconitum carmichaelii, which has been widely used to treat various diseases on account of its analgesic, anti-inflammatory, anti-rheumatic, and immunosuppressive properties. The aim of this study was to evaluate the analgesic effect of isotalatizidine and its underlying mechanisms against neuropathic pain. Methods A chronic constrictive injury (CCI)-induced model of neuropathic pain was established in mice, and the limb withdrawal was evaluated by the Von Frey filament test following isotalatizidine or placebo administration. The signaling pathways in primary or immortalized microglia cells treated with isotalatizidine were analyzed by Western blotting and immunofluorescence. Results Intrathecal injection of isotalatizidine attenuated the CCI-induced mechanical allodynia in a dose-dependent manner. At the molecular level, isotalatizidine selectively increased the phosphorylation of p38 and ERK1/2, in addition to activating the transcription factor CREB and increasing dynorphin A production in cultured primary microglia. However, the downstream effects of isotalatizidine were abrogated by the selective ERK1/2 inhibitor U0126-EtOH or CREB inhibitor of KG-501, but not by the p38 inhibitor SB203580. The results also were confirmed in in vivo experiments. Conclusion Taken together, isotalatizidine specifically activates the ERK1/2 pathway and subsequently CREB, which triggers dynorphin A release in the microglia, eventually leading to its anti-nociceptive action.

Download Full-text

CaM kinase II regulates cardiac hemoglobin expression through histone phosphorylation upon sympathetic activation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1816521116 ◽

2019 ◽

Vol 116 (44) ◽

pp. 22282-22287

Author(s):

Ali Reza Saadatmand ◽

Viviana Sramek ◽

Silvio Weber ◽

Daniel Finke ◽

Matthias Dewenter ◽

...

Keyword(s):

Messenger Rna ◽

Target Genes ◽

Ventricular Myocardium ◽

Cam Kinase Ii ◽

Sympathetic Activation ◽

Cam Kinase ◽

In Vivo Experiments ◽

Underlying Mechanisms

Sympathetic activation of β-adrenoreceptors (β-AR) represents a hallmark in the development of heart failure (HF). However, little is known about the underlying mechanisms of gene regulation. In human ventricular myocardium from patients with end-stage HF, we found high levels of phosphorylated histone 3 at serine-28 (H3S28p). H3S28p was increased by inhibition of the catecholamine-sensitive protein phosphatase 1 and decreased by β-blocker pretreatment. By a series of in vitro and in vivo experiments, we show that the β-AR downstream protein kinase CaM kinase II (CaMKII) directly binds and phosphorylates H3S28. Whereas, in CaMKII-deficient myocytes, acute catecholaminergic stimulation resulted in some degree of H3S28p, sustained catecholaminergic stimulation almost entirely failed to induce H3S28p. Genome-wide analysis of CaMKII-mediated H3S28p in response to chronic β-AR stress by chromatin immunoprecipitation followed by massive genomic sequencing led to the identification of CaMKII-dependent H3S28p target genes. Forty percent of differentially H3S28p-enriched genomic regions were associated with differential, mostly increased expression of the nearest genes, pointing to CaMKII-dependent H3S28p as an activating histone mark. Remarkably, the adult hemoglobin genes showed an H3S28p enrichment close to their transcriptional start or end sites, which was associated with increased messenger RNA and protein expression. In summary, we demonstrate that chronic β-AR activation leads to CaMKII-mediated H3S28p in cardiomyocytes. Thus, H3S28p-dependent changes may play an unexpected role for cardiac hemoglobin regulation in the context of sympathetic activation. These data also imply that CaMKII may be a yet unrecognized stress-responsive regulator of hematopoesis.

Download Full-text

Bioactive Surfaces vs. Conventional Surfaces in Titanium Dental Implants: A Comparative Systematic Review

Journal of Clinical Medicine ◽

10.3390/jcm9072047 ◽

2020 ◽

Vol 9 (7) ◽

pp. 2047 ◽

Cited By ~ 2

Author(s):

Nansi López-Valverde ◽

Javier Flores-Fraile ◽

Juan Manuel Ramírez ◽

Bruno Macedo de Sousa ◽

Silvia Herrero-Hernández ◽

...

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Dental Implants ◽

Animal Studies ◽

Statistical Significance ◽

Cochrane Collaboration ◽

In Vivo Experiments ◽

Bone To Implant Contact ◽

Bioactive Surfaces

Animal studies and the scarce clinical trials available that have been conducted suggest that bioactive surfaces on dental implants could improve the osseointegration of such implants. The purpose of this systematic review was to compare the effectiveness of osseointegration of titanium (Ti) dental implants using bioactive surfaces with that of Ti implants using conventional surfaces such as sandblasted large-grit acid-etched (SLA) or similar surfaces. Applying the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, the MEDLINE, PubMed Central and Web of Science databases were searched for scientific articles in April 2020. The keywords used were “dental implants”, “bioactive surfaces”, “biofunctionalized surfaces”, and “osseointegration”, according to the question: “Do bioactive dental implant surfaces have greater osseointegration capacity compared with conventional implant surfaces?” Risk of bias was assessed using the Cochrane Collaboration tool. 128 studies were identified, of which only 30 met the inclusion criteria: 3 clinical trials and 27 animal studies. The average STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) and ARRIVE (Animal Research: Reporting of In Vivo Experiments) scores were 15.13 ± 2.08 and 17.7±1.4, respectively. Implant stability quotient (ISQ) was reported in 3 studies; removal torque test (RTT)—in 1 study; intraoral periapical X-ray and microcomputed tomography radiological evaluation (RE)—in 4 studies; shear force (SF)—in 1 study; bone-to-implant contact (BIC)—in 12 studies; and BIC and bone area (BA) jointly—in 5 studies. All animal studies reported better bone-to-implant contact surface for bioactive surfaces as compared to control implants with a statistical significance of p < 0.05. Regarding the bioactive surfaces investigated, the best results were yielded by the one where mechanical and chemical treatment methods of the Ti surfaces were combined. Hydroxyapatite (HA) and calcium–phosphate (Ca–Ph) were the most frequently used bioactive surfaces. According to the results of this systematic review, certain bioactive surfaces have a positive effect on osseointegration, although certain coating biomolecules seem to influence early peri-implant bone formation. Further and more in-depth research in this field is required to reduce the time needed for osseointegration of dental implants.

Download Full-text

BMP activity controlled by BMPER regulates the proinflammatory phenotype of endothelium

Blood ◽

10.1182/blood-2011-03-339762 ◽

2011 ◽

Vol 118 (18) ◽

pp. 5040-5049 ◽

Cited By ~ 47

Author(s):

Thomas Helbing ◽

René Rothweiler ◽

Elena Ketterer ◽

Lena Goetz ◽

Jennifer Heinke ◽

...

Keyword(s):

Vascular Endothelial Cells ◽

Ex Vivo ◽

Leukocyte Adhesion ◽

Vascular Inflammation ◽

Bmp Signaling ◽

In Vivo Models ◽

In Vivo Experiments ◽

And Migration

Abstract The endothelium plays a pivotal role in vascular inflammation. Here we study bone morphogenetic protein (BMP) signaling in endothelial inflammation and in particular the role of BMPER, an extracellular BMP modulator that is important in vascular development and angiogenesis. Using the BMP antagonist dorsomorphin or BMP2 as an agonist we show that BMP signaling is essential for the inflammatory response of vascular endothelial cells as demonstrated by intravital microscopy. We found that BMPER is decreased in inflammation similar to vascular protective genes like KLF2 and eNOS. Using in vitro and in vivo models we show that BMPER is down-regulated through the TNFα-NFκB-KLF2 signaling pathway. Functionally, lack of BMPER induced by siRNA or in BMPER+/− mice confers a proinflammatory endothelial phenotype with reduced eNOS levels and enhanced expression of adhesion molecules leading to increased leukocyte adhesion and extravasation in ex vivo and in vivo experiments. Vice versa, addition of BMPER exerts endothelium protective functions and antagonizes TNFα induced inflammation. Mechanistically, we demonstrate that these effects of BMPER are dependent on BMP signaling because of enhanced NFκB activity. In conclusion, the BMP modulator BMPER is a new protective regulator of vascular inflammation that modulates leukocyte adhesion and migration in vitro and in vivo.

Download Full-text