Myriocin and D-PDMP Ameliorate Atherosclerosis in ApoE -/- Mice via Reducing Lipid Uptake and Vascular Inflammation

2019 ◽  
Author(s):  
Zemou Yu ◽  
Qing Peng ◽  
Songyue Li ◽  
Hongjun Hao ◽  
Jianwen Deng ◽  
...  
Keyword(s):  
Vascular Inflammation ◽  
Lipid Uptake

scholarly journals Myriocin and d-PDMP ameliorate atherosclerosis in ApoE−/− mice via reducing lipid uptake and vascular inflammation

2020 ◽  
Vol 134 (5) ◽  
pp. 439-458 ◽  
Author(s):  
Zemou Yu ◽  
Qing Peng ◽  
Songyue Li ◽  
Hongjun Hao ◽  
Jianwen Deng ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Foam Cell ◽  
Oxidized Ldl ◽  
Vascular Inflammation ◽  
Cell Formation ◽  
Ldl Receptor ◽  
Foam Cell Formation ◽  
Lipid Uptake ◽  
Atherosclerosis Progression

Abstract Sphingolipids have been implicated in the etiology of atherosclerosis. The commonly used sphingolipid inhibitors, myriocin (a ceramide inhibitor) and d-PDMP (d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, a glycosphingolipid inhibitor), have shown therapeutic potential but their efficacy and their underlying mechanisms remain unclear. Here, apolipoprotein E-deficient (apoE−/−) mice were fed a high-fat diet (HFD) and treated with a control, myriocin, d-PDMP, or atorvastatin for 12 weeks. We analyzed the effects of these drugs on the size and detailed composition of atherosclerotic plaques. Molecular biological approaches were used to explore how the inhibitors affect lipid metabolism and foam-cell formation. Treatment with myriocin or d-PDMP led to smaller and less vulnerable atherosclerotic lesions and was almost as effective as atorvastatin. Sphingolipid inhibitors down-regulated the expression of monocyte chemotactic protein 1 (MCP-1) and its receptor chemoattractant cytokine receptor 2 (CCR2), which play a key role in monocyte recruitment. They also decreased pro-inflammatory Ly-6chigh monocytes and influenced the uptake of modified LDL by down-regulating the expression of cluster of differentiation 36 (CD36) and lectin-like oxidized LDL (ox-LDL) receptor-1 (LOX-1). The inhibitors exhibited the advantage of maintaining normal glucose homeostasis compared with atorvastatin. These findings reveal for the first time that the modulation of sphingolipid synthesis can effectively alleviate atherosclerosis progression by preventing lipid uptake and reducing inflammatory responses in the arterial walls.

scholarly journals Crosstalk Between LXR and Caveolin-1 Signaling Supports Cholesterol Efflux and Anti-Inflammatory Pathways in Macrophages

2021 ◽  
Vol 12 ◽  
Author(s):  
Cristina M. Ramírez ◽  
Marta Torrecilla-Parra ◽  
Virginia Pardo-Marqués ◽  
Mario Fernández de-Frutos ◽  
Ana Pérez-García ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Inflammatory Responses ◽  
Apoptotic Cell ◽  
Vascular Inflammation ◽  
Cholesterol Homeostasis ◽  
Lipid Uptake ◽  
Loss Of Function ◽  
Caveolin 1 ◽  
Downstream Signaling ◽  
Cell Clearance

Macrophages are immune cells that play crucial roles in host defense against pathogens by triggering their exceptional phagocytic and inflammatory functions. Macrophages that reside in healthy tissues also accomplish important tasks to preserve organ homeostasis, including lipid uptake/efflux or apoptotic-cell clearance. Both homeostatic and inflammatory functions of macrophages require the precise stability of lipid-rich microdomains located at the cell membrane for the initiation of downstream signaling cascades. Caveolin-1 (Cav-1) is the main protein responsible for the biogenesis of caveolae and plays an important role in vascular inflammation and atherosclerosis. The Liver X receptors (LXRs) are key transcription factors for cholesterol efflux and inflammatory gene responses in macrophages. Although the role of Cav-1 in cellular cholesterol homeostasis and vascular inflammation has been reported, the connection between LXR transcriptional activity and Cav-1 expression and function in macrophages has not been investigated. Here, using gain and loss of function approaches, we demonstrate that LXR-dependent transcriptional pathways modulate Cav-1 expression and compartmentation within the membrane during macrophage activation. As a result, Cav-1 participates in LXR-dependent cholesterol efflux and the control of inflammatory responses. Together, our data show modulation of the LXR-Cav-1 axis could be exploited to control exacerbated inflammation and cholesterol overload in the macrophage during the pathogenesis of lipid and immune disorders, such as atherosclerosis.

Abstract 306: Deficiency of ROCK1 in Macrophages Protects Against Atherosclerosis

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Hong-Wei Wang ◽  
Naotsugu Oyama ◽  
Yoshiyuki Rikitake ◽  
Shiro Kitamoto ◽  
Jonathan Gitlin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Foam Cell ◽  
Vascular Inflammation ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cells ◽  
Foam Cell Formation ◽  
Low Density ◽  
Lipid Uptake

Background: Rho kinases (ROCKs) are serine-threonine protein kinases that regulate various cellular functions. There is increasing evidence that the RhoA/ROCK pathway plays an important pathophysiological role in cardiovascular diseases. However, direct evidence of which ROCK isoforms or target tissues are involved in the atherogenic process is still lacking. Objective: The aim of this study was to determine the effect of ROCK1 deficiency on atherogenesis and how ROCK1 affects key atherosclerosis-related macrophage function such as lipid uptake and chemotaxis. Methods: We utilized ROCK1 −/− mice and the atherosclerosis-prone apolipoprotein E knockout (apoE −/− ) mice or low-density lipoprotein receptor knockout (LDLR −/− ) mice to investigate the role of ROCK1 in the pathogenesis of atherosclerotic plaque formation. Bone marrow-derived macrophages from ROCK1 −/− and ROCK1 +/+ mice were used to investigate acetylated (Ac)LDL-mediated foam cell formation and chemotaxis. Results: Compared to atherosclerosis-prone apoE −/− mice, apoE −/− ROCK1 +/− mice had substantially less fatty streaks foam cells and atherosclerosis (77.0 ± 12.9 × 10 3 μm 2 versus 166.4 ± 14.6 × 10 3 μm 2 , P < 0.01). Atherosclerotic lesions were reduced also in LDLR −/− mice, whose bone marrow were replaced with bone marrow derived from ROCK1 −/− mice compared to ROCK1 +/+ recipients (181.5 ± 15.6 × 10 3 μm 2 versus 448.5 ± 33.3 × 10 3 μm 2 , P < 0.05). Bone marrow-derived ROCK1-deficient macrophages exhibited impaired chemotaxis to monocyte chemotactic protein-1 and showed reduced ability to take up lipids and to develop into foam cells when exposed to modified low density lipoprotein. Conclusion: These findings indicate that ROCK1 in macrophages is a critical mediator of foam cell formation, macrophage chemotaxis and atherogenesis, and suggest that macrophage ROCK1 may be an important therapeutic target for vascular inflammation and atherosclerosis.

Sorghum Fermented by Aspergillus oryzae NK Enhances Inhibition of Vascular Inflammation in TNF-α-stimulated Human Aortic Smooth Muscle Cells

2018 ◽  
Vol 88 (5-6) ◽  
pp. 309-318
Author(s):  
Hae Seong Song ◽  
Jung-Eun Kwon ◽  
Hyun Jin Baek ◽  
Chang Won Kim ◽  
Hyelin Jeon ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Inflammatory Response ◽  
Smooth Muscle Cells ◽  
Adhesion Molecule ◽  
Vascular Inflammation ◽  
Muscle Cells ◽  
Aortic Smooth Muscle Cells ◽  
Aortic Smooth Muscle ◽  
Tnf Α ◽  
Cox 2

Abstract. Sorghum bicolor L. Moench is widely grown all over the world for food and feed. The effects of sorghum extracts on general inflammation have been previously studied, but its anti-vascular inflammatory effects are unknown. Therefore, this study investigated the anti-vascular inflammation effects of sorghum extract (SBE) and fermented extract of sorghum (fSBE) on human aortic smooth muscle cells (HASMCs). After the cytotoxicity test of the sorghum extract, a series of experiments were conducted. The inhibition effects of SBE and fSBE on the inflammatory response and adhesion molecule expression were measured using treatment with tumor necrosis factor-α (TNF-α), a crucial promoter for the development of atherosclerotic lesions, on HASMCs. After TNF-α (10 ng/mL) treatment for 2 h, then SBE and fSBE (100 and 200 μg/mL) were applied for 12h. Western blotting analysis showed that the expression of vascular cell adhesion molecule-1 (VCAM-1) (2.4-fold) and cyclooxygenase-2 (COX-2) (6.7-fold) decreased, and heme oxygenase-1 (HO-1) (3.5-fold) increased compared to the TNF-α control when treated with 200 μg/mL fSBE (P<0.05). In addition, the fSBE significantly increased the expression of HO-1 and significantly decreased the expression of VCAM-1 and COX-2 compared to the TNF-α control in mRNA level (P<0.05). These reasons of results might be due to the increased concentrations of procyanidin B1 (about 6-fold) and C1 (about 30-fold) produced through fermentation with Aspergillus oryzae NK for 48 h, at 37 °C. Overall, the results demonstrated that fSBE enhanced the inhibition of the inflammatory response and adherent molecule expression in HASMCs.

Role of Caveolin-3 in lipid uptake and accumulation in muscle cells

2013 ◽  
Vol 8 (S 01) ◽  
Author(s):  
E Januszewicz ◽  
M Boschmann ◽  
A Foryst-Ludwig ◽  
V Benz ◽  
M Bloch ◽  
...  
Keyword(s):  
Muscle Cells ◽  
Lipid Uptake

PERAN AIR REBUSAN DAUN SALAM (SYZGIUM POLYANTHUM) DALAM MENURUNKAN KADAR ASAM URAT

2016 ◽  
Vol 5 (2) ◽  
pp. 83-91
Author(s):  
Miftafu Darussalam ◽  
Dwi Kartika Rukmi
Keyword(s):  
Uric Acid ◽  
Vascular Inflammation ◽  
Vascular Lesion ◽  
Wilcoxon Test ◽  
Test Time ◽  
Control Group ◽  
Target Area ◽  
Bioactive Substances ◽  
Control Group Design ◽  
Boiled Water

Background: Uric acid is a final product or a waste that is resulted from the metabolism of purines. A high level of uric acid (hyperuricemia) will cause several health problems, such as vascular inflammation, smooth muscle proliferation, and vascular lesion in kidneys. The syzygium polyanthum leaves contain bioactive substances that may affect the level of uric acid in blood. Objective: This study aimed to determine the influence of boiled water of syzygium polyanthum leaves to the changes of uric acid levels in the target area of Puskesmas Pandak 1 Bantul. Methods: This study employed pre- and post-test without control group design. The population consisted of all patients with hyperuricemia in the target area of Puskesmas Pandak 1 Bantul. Sample was selected with a concecutive sampling, gaining a total number of 24 respondents. Data were analyzed with the Wilcoxon test. The dose of boiled water of syzygium polyanthum leaves intake was 0.36g/ KgBW, once a day for 14 days. Result: This research showed that the boiled water of syzygium polyanthum leaves decreased hyperuricemia (uric acid levels), along with the significancy value of 0.009 (p <0.05). At the pre-test time, the average level of uric acid reached 7.279 mg/dl, and after the treatment, it decreased to 6.76 mg/dl. Conclusion: This study has established evidence that the boiled water of syzygium polyanthum leaves is able to decrease hyperuricemia (uric acid level in blood). Keywords: syzygium polyanthum, boiled water of syzygium polyanthum leaves, hyperuricemia

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