Endothelial cell dysfunction as a novel therapeutic target in atherosclerosis

Jensen, Hanna; Mehta, Jawahar L.

doi:10.1080/14779072.2016.1207527

Cited by 74 publications

(69 citation statements)

References 136 publications

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“…Atherosclerosis (AS) is a progressive condition involving accumulation of lipids and fibrous elements in the large arteries, which is a key trigger for CVD [3]. Endothelial cell dysfunction is an important characteristic of AS [4, 5]. Both oxidative stress and mitochondrial dysfunction are responsible for the development of endothelial dysfunction [6, 7].…”

Section: Introductionmentioning

confidence: 99%

Allicin Decreases Lipopolysaccharide-Induced Oxidative Stress and Inflammation in Human Umbilical Vein Endothelial Cells through Suppression of Mitochondrial Dysfunction and Activation of Nrf2

Zhang¹,

Pan²,

Xu³

et al. 2017

Cell Physiol Biochem

106

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Background: Allicin, a major component of garlic, is regarded as a cardioprotective agent and is associated with increased endothelial function. Methods: The effects of allicin on lipopolysaccharide (LPS)-induced vascular oxidative stress and inflammation in cultured human umbilical vein endothelial cells (HUVECs) and the mechanisms underlying these effects were studied. The protective effects were measured using cell viability, a lactate dehydrogenase (LDH) assay and cell apoptosis as indicators, and the anti-oxidative activity was determined by measuring reactive oxygen species (ROS) generation, oxidative products and endogenous antioxidant enzyme activities. HUVEC mitochondrial function was assessed by determining mitochondrial membrane potential (MMP) collapse, cytochrome c production and mitochondrial ATP release. To investigate the potential underlying mechanisms, we also measured the expression of dynamic mitochondrial proteins using western blotting. Furthermore, we evaluated the Nrf2 antioxidant signaling pathway using an enzyme-linked immunosorbent assay (ELISA). Results: Our results demonstrated that allicin enhanced HUVEC proliferation, which was suppressed by LPS exposure, and LDH release. Allicin ameliorated LPS-induced apoptosis, suppressed ROS overproduction, reduced lipid peroxidation and decreased the endogenous antioxidant enzyme activities in HUVECs. These protective effects were associated with the inhibition of mitochondrial dysfunction as indicated by decreases in the MMP collapse, cytochrome c synthesis and mitochondrial ATP release. In addition, allicin attenuated the LPS-induced inflammatory responses, including endothelial cell adhesion and TNF-α and IL-8 production. Furthermore, allicin increased the expression of LXRα in a dose-dependent manner. Allicin-induced attenuation of inflammation was inhibited by LXRα siRNA treatment. Finally, allicin activated NF-E2-related factor 2 (Nrf2), which controls the defense against oxidative stress and inflammation. Conclusions: Taken together, the present data suggest that allicin attenuated the LPS-induced vascular injury process, which may be closely related to the oxidative stress and inflammatory response in HUVECs. Allicin modulated Nrf2 activation and protected the cells against LPS-induced vascular injury. Our findings suggest that allicin attenuated the LPS-induced inflammatory response in blood vessels.

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Section: Introductionmentioning

confidence: 99%

Allicin Decreases Lipopolysaccharide-Induced Oxidative Stress and Inflammation in Human Umbilical Vein Endothelial Cells through Suppression of Mitochondrial Dysfunction and Activation of Nrf2

Zhang¹,

Pan²,

Xu³

et al. 2017

Cell Physiol Biochem

106

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“…Therefore, it is necessary to focus on the potential targets of endothelial dysfunction, which in turn would provide novel prevention and treatment strategies [33]. …”

Section: Discussionmentioning

confidence: 99%

Ox-LDL-Induced MicroRNA-155 Promotes Autophagy in Human Endothelial Cells via Repressing the Rheb/ mTOR Pathway

Lv¹,

Yang²,

Guo³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Autophagy, an evolutionary conserved biological process, is activated in cells to cope with various types of stress. MicroRNAs control several activities related to autophagy. However, the role of autophagy-related microRNAs during atherosclerosis is far from known. MicroRNA-155 was identified to be a crucial regulator of atherosclerosis. The objectives of the study were to analyze the effect of microRNA-155 on autophagic signaling and explore its mechanism in human endothelial cells under ox-LDL stress. Methods: The study included human endothelial cells surrogate EA.hy926 lines (EA.hy926 cells). The expression of microRNA-155 was analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The effect of microRNA-155 on endothelial autophagy was observed along with the expression levels of Rheb, LC3B, Beclin1, and P62/SQSTM1 by western blotting (WB) and immunofluorescence through microRNA-155 overexpression or inhibition. Bioinformatics analysis and Luciferase reporter assay were used to explore the target gene of microRNA-155. Cell viability and apoptosis were examined by 3-[4,5-dimethylthiazol-2-yl]-5- [3-carboxy-methoxyphenyl]-2-[4-sulfophenyl]-2H-tetrazolium inner salt (MTS) assay and TdT-mediated dUTP Nick-End Labeling (TUNEL) apoptosis assay. Results: MicroRNA-155 expression was significantly increased under ox-LDL stress. MicroRNA-155 increased autophagic activity, while inhibition of it alleviated ox-LDL-induced autophagy in EA.hy926 endothelial cells. In addition, dual-luciferase reporter assays showed that microRNA-155 suppressed Rheb transcription. MicroRNA-155 increased autophagic activity in EA.hy926 cells via inhibition of Rheb-mediated mTOR/P70S6kinase/4EBP signaling pathway. Furthermore, we demonstrated that microRNA-155 could regulate not only autophagy but also apoptosis in EA.hy926 cells. Conclusions: MicroRNA-155 works as a regulator of endothelial function under ox-LDL stress, making it a potential candidate for the novel therapeutic strategies against atherosclerotic diseases.

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“…Increased metabolic risk in the offspring is often brought about by maternal gestational diabetes (GDM) (4) and apart from the well-documented short-term adverse obstetric and perinatal complications associated with GDM (5), long-term future metabolic health and neurodevelopmental implications for the offspring have been described (6). The intrauterine exposure to maternal diabetes has also been linked to higher cardiovascular stress responses in the offspring (7) and cardiovascular disease can become apparent in form of endothelial dysfunction (ED) (8,9). Elevation of markers have been linked to inflammation and ED in ADVANCE ARTICLE: Endocrinology 2 umbilical cord blood (10) and ED early in life may accelerate the onset of cardiovascular disease (11), which is supported by the evidence that offspring of mothers with GDM have an increased cardiovascular disease risk (12,13).…”

mentioning

confidence: 99%

Gestational Diabetes Alters Functions in Offspring’s Umbilical Cord Cells With Implications for Cardiovascular Health

et al. 2017

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Because noncommunicable diseases such as type 2 diabetes mellitus have their roots in prenatal development and conditions such as maternal gestational diabetes mellitus (GDM), we aimed to test this hypothesis in primary cells derived from the offspring of mothers with GDM compared with control subjects. We have assessed primary umbilical cord-derived cells such as human umbilical vein endothelial cells (HUVECs) and Wharton's jelly-derived mesenchymal stem cells from the offspring of mothers with and without GDM. We have compared the primary isolates in cell-based assays measuring proliferation, mitochondrial oxygen consumption, and the ability to support blood vessel growth. We conducted gene expression microarray studies with subsequent pathway analysis and candidate gene validation. We observed striking differences between the two groups, such as lower metabolic rates and impairment of endothelial tube formation in cells with GDM background. HUVECs from subjects with maternal GDM have lower expression of the antiapoptotic protein BCL-xL, suggesting compromised angiogenic capabilities. Comparative gene expression analysis revealed blood vessel formation as a major pathway enriched in the GDM-derived HUVECs with the surface marker CD44 as a gene underexpressed in the GDM group. Functional validation of CD44 revealed that it regulates tube formation in HUVECs, thereby providing insights into a pathway imprinted in primary umbilical cord-derived cells from GDM offspring. Our data demonstrate that primary cells isolated from the umbilical cord of offspring born to mothers with GDM maintain metabolic and molecular imprints of maternal hyperglycemia, reflecting an increased risk for cardiovascular disease later in life.

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Endothelial cell dysfunction as a novel therapeutic target in atherosclerosis

Cited by 74 publications

References 136 publications

Allicin Decreases Lipopolysaccharide-Induced Oxidative Stress and Inflammation in Human Umbilical Vein Endothelial Cells through Suppression of Mitochondrial Dysfunction and Activation of Nrf2

Allicin Decreases Lipopolysaccharide-Induced Oxidative Stress and Inflammation in Human Umbilical Vein Endothelial Cells through Suppression of Mitochondrial Dysfunction and Activation of Nrf2

Ox-LDL-Induced MicroRNA-155 Promotes Autophagy in Human Endothelial Cells via Repressing the Rheb/ mTOR Pathway

Gestational Diabetes Alters Functions in Offspring’s Umbilical Cord Cells With Implications for Cardiovascular Health

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