Latest Updates on Lipid Management

Egom, Emmanuel E.; Pharithi, Rebabonye B; Hesse, Soressa; Starr, Neasa; Armstrong, Richard; Sulaiman, H; Gazdíková, Katarína; Mozoş, Ioana; Čaprnda, Martin; Kubatka, Peter; Kružliak, Peter; Khan, Barkat Ullah; Gašpar, Ľudovít; Maher, Vincent

doi:10.1007/s40292-019-00306-8

Cited by 4 publications

(4 citation statements)

References 167 publications

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“…Atherosclerosis is a chronic inflammatory disease and different cells are involved in the disease processes, including endothelial cells (Paone et al, 2019), monocytes (Escarcega et al, 2018), macrophages (Biessen and Wouters, 2017), and smooth muscle cells (Lao et al, 2015). The latest epidemiological statistics in 2019 show that dyslipidemia remains a major risk factor for atherosclerotic cardiovascular disease (Egom et al, 2019). Dyslipidemia cover a wide range of lipoprotein abnormalities, including elevated levels of low-density lipoprotein cholesterol, total cholesterol, and total triglyceride, as well as decreased levels of high density lipoprotein cholesterol, especially the LDL receptors were firmly up-regulated in cholesterol metabolism (Goldstein and Brown, 2015), thus LDL can be ingested and modificated into ox-LDL exhibit a variety of proatherogenic properties on vascular cultured cells (Salvayre et al, 2016), and the intervention of ox-LDL for vascular cells in study of AS in vitro has been widely used.…”

Section: Discussionmentioning

confidence: 99%

Ginsenoside Rg3 Alleviates ox-LDL Induced Endothelial Dysfunction and Prevents Atherosclerosis in ApoE−/− Mice by Regulating PPARγ/FAK Signaling Pathway

Geng

et al. 2020

Front. Pharmacol.

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The initiation of atherosclerosis (AS) induced by dyslipidemia is accompanied by endothelial dysfunction, including decreased healing ability and increased recruitment of monocytes. Studies showed ginsenoside Rg3 has potential to treat diseases associated with endothelial dysfunction which can protects against antineoplastic drugs induced cardiotoxicity by repairing endothelial function, while the effect and mechanism of Rg3 on dyslipidemia induced endothelial dysfunction and AS are not clear. Therefore, we investigated the effects of Rg3 on oxidized low-density lipoprotein (ox-LDL) induced human umbilical vein endothelial cells (HUVECs) dysfunction and high-fat diets (HFD) induced atherosclerosis in ApoE −/− mice, as well as the mechanism. For in vitro assay, Rg3 enhanced healing of HUVECs and inhibited human monocytes (THP-1) adhesion to HUVECs disturbed by ox-LDL, down-regulated focal adhesion kinase (FAK)-mediated expression of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1); restrained the FAK-mediated non-adherent dependent pathway containing matrix metalloproteinase (MMP)-2/9 expression, activation of nuclear factorkappa B (NF-kB), high mRNA levels of monocyte chemotactic protein 1 (MCP-1) and interleukin 6 (IL-6), besides Rg3 up-regulated peroxisome proliferators-activated receptor g (PPARg) in ox-LDL-stimulated HUVECs. GW9662, the PPARg-specific inhibitor, can repressed the effects of Rg3 on ox-LDL-stimulated HUVECs. For in vivo assay, Rg3 significantly reduced atherosclerotic pathological changes in ApoE −/− mice fed with HFD, up-regulated PPARg, and inhibited activation FAK in aorta, thus inhibited expression of VCAM-1, ICAM-1 in intima. We conclude that Rg3 may protect endothelial cells and inhibit atherosclerosis by up-regulating PPARg via repressing FAK-mediated pathways, indicating that Rg3 have good potential in preventing dyslipidemia induced atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

Ginsenoside Rg3 Alleviates ox-LDL Induced Endothelial Dysfunction and Prevents Atherosclerosis in ApoE−/− Mice by Regulating PPARγ/FAK Signaling Pathway

Geng

et al. 2020

Front. Pharmacol.

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“…Statins act mainly by inhibiting the cholesterol synthetic pathway. It is hypothesized that statins may also have pleiotropic effects, such as reduction of the inflammatory process and esterification of cholesterol to macrophages (11). Therefore, the investigation of their extensive mechanism of action could potentially increase the efficacy of their therapeutic effects (12).…”

Section: Rosuvastatin Protects Against Endothelial Cell Apoptosis In mentioning

confidence: 99%

Rosuvastatin protects against endothelial cell apoptosis in vitro and alleviates atherosclerosis in ApoE‑/‑ mice by suppressing endoplasmic reticulum stress

Geng

et al. 2020

Exp Ther Med

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The development of abnormal lipid-induced atherosclerosis is initiated with endothelial cell apoptosis. Vascular endothelial cells possess highly developed endoplasmic reticulum (ER), which is involved in lipid metabolism, indicating that ER stress may contribute chiefly to the induction of endothelial cell apoptosis. Based on its ability to reduce cholesterol levels, rosuvastatin may play an endothelial and vascular protective role by regulating ER stress. In the present study, the involvement of the inhibition of the ER stress-induced endothelial injury was investigated in combination with the lipid lowering effects of rosuvastatin. This compound can be used to inhibit cholesterol synthesis in atherosclerosis. Rosuvastatin decreased the apoptotic rates of human umbilical vascular endothelial cells (HUVECs) that had been stimulated with ox-low density lipoprotein (LDL) in vitro and repressed the mRNA levels of CHOP, sXBP1 and caspase-12, and decreased caspase-12 activity, as well as the content of glucose-regulated protein 78 (GRP78), phosphorylated (p)-protein kinase RNA-like ER kinase (PERK), p-inositol-requiring protein 1α (IRE1α) and p-eIF2α proteins. In addition, ApoE-/mice were fed with atherogenic chow for 8 weeks for atherosclerosis induction and rosuvastatin was provided by intragastric administration for an additional 4 weeks. Subsequently, the atherosclerotic plaque formation in the aorta was evaluated by Oil Red O and hematoxylin and eosin staining, and the serum LDL, high-density lipoprotein, total cholesterol (TC) and triacylglycerol (TG) levels were measured. In addition, the induction of apoptosis of endothelial cells and the expression levels of GRP78, p-PERK, p-IRE1α and p-eIF2α were assessed in the aorta. Rosuvastatin repressed atherosclerotic plaque formation and endothelial apoptosis in the aorta and decreased LDL and TG levels in the serum, as determined by in vivo results. Furthermore, it downregulated the expression levels of protein chaperone GRP78, p-PERK, p-IRE1α and p-eIF2α in the aortic intima. The data indicated that rosuvastatin could protect HUVECs from ER stress-induced apoptosis triggered by oxidized LDL. It could also inhibit atherosclerosis formation in ApoE-/mice aorta by regulating the PERK/eIF2α/C/EBPα-homologous protein and IRE1α/sXBP1 signaling pathways. Taken collectively, the present study demonstrated the preventive and therapeutic effects of rosuvastatin in protecting from the development of endothelial cell dysfunction diseases.

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“…Hypercholesterolemia with elevated plasma low-density lipoprotein cholesterol (LDL-C) levels is a major risk factor for cardiovascular diseases (CVDs) [ 1 , 2 ]. Accumulating experimental and clinical studies implicate that a high level of LDL-C in the serum is closely associated with the incidence of CVDs [ 3 , 4 , 5 ]. Plasma LDL-C is mainly cleared through binding to the low-density lipoprotein receptor (LDLR) on the surface of hepatocytes, and the formed LDL-C/LDL-R complex is subsequently transported to lysosome for LDL-C degradation, and the LDLR is recycled to the cell surface [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Generation of a Novel High-Affinity Antibody Binding to PCSK9 Catalytic Domain with Slow Dissociation Rate by CDR-Grafting, Alanine Scanning and Saturated Site-Directed Mutagenesis for Favorably Treating Hypercholesterolemia

Bai

Mei

et al. 2021

Biomedicines

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Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has become an attractive therapeutic strategy for lowering low-density lipoprotein cholesterol (LDL-C). In this study, a novel high affinity humanized IgG1 mAb (named h5E12-L230G) targeting the catalytic domain of human PCSK9 (hPCSK9) was generated by using CDR-grafting, alanine-scanning mutagenesis, and saturated site-directed mutagenesis. The heavy-chain constant region of h5E12-L230G was modified to eliminate the cytotoxic effector functions and mitigate the heterogeneity. The biolayer interferometry (BLI) binding assay and molecular docking study revealed that h5E12-L230G binds to the catalytic domain of hPCSK9 with nanomolar affinity (KD = 1.72 nM) and an extremely slow dissociation rate (koff, 4.84 × 10−5 s−1), which interprets its quite low binding energy (−54.97 kcal/mol) with hPCSK9. Additionally, h5E12-L230G elevated the levels of LDLR and enhanced the LDL-C uptake in HepG2 cells, as well as reducing the serum LDL-C and total cholesterol (TC) levels in hyperlipidemic mouse model with high potency comparable to the positive control alirocumab. Our data indicate that h5E12-L230G is a high-affinity anti-PCSK9 antibody candidate with an extremely slow dissociation rate for favorably treating hypercholesterolemia and relevant cardiovascular diseases.

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Latest Updates on Lipid Management

Cited by 4 publications

References 167 publications

Ginsenoside Rg3 Alleviates ox-LDL Induced Endothelial Dysfunction and Prevents Atherosclerosis in ApoE−/− Mice by Regulating PPARγ/FAK Signaling Pathway

Ginsenoside Rg3 Alleviates ox-LDL Induced Endothelial Dysfunction and Prevents Atherosclerosis in ApoE−/− Mice by Regulating PPARγ/FAK Signaling Pathway

Rosuvastatin protects against endothelial cell apoptosis in vitro and alleviates atherosclerosis in ApoE‑/‑ mice by suppressing endoplasmic reticulum stress

Generation of a Novel High-Affinity Antibody Binding to PCSK9 Catalytic Domain with Slow Dissociation Rate by CDR-Grafting, Alanine Scanning and Saturated Site-Directed Mutagenesis for Favorably Treating Hypercholesterolemia

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