Hyperlipidemia And Specifically Hypercholesterolemia

AhR

Describe about the Hyperlipidemia and Specifically Hypercholesterolemia?

AhR

In the case of hyperlipidemia and specifically hypercholesterolemia it has been associated to some the specific receptor or ligands and AhR is referred as Aryl hydrocarbon receptor that acts as a ligand to cause hyperlipidemia (Wu et al., 2011)

ApoE-/-

Apolipoprotein E is the lipoprotein that is produced by liver and macrophages and is a key player in cholesterol metabolism by mediating in catabolism of triglyceride lipoproteins. In the present study ApoE-/- knock-out mice has been selected lacking ApoE protein and it has validated that AhR induces atherosclerosis by vascular inflammation in used murine model (Boring et al., 1998)

CH223191

In the study CH223191 is an AhR antagonist and has been administered 24 h before TCDD and is known to overcome the toxic effect of TCDD in liver in vivo. CH223191 treated mice and TCDD mice were compared and found that CH223191 reduces cholesterol accumulation and formation of atherosclerosis lesion formation.

CSE

It indicates for  cigarette smoke extract and is an AhR activator. In present study it increases the expression of MCP-1, IL-8,CXCL-5 and MMP-12 in U937 monocyte cells. It is also known to induce expression VEGF and stimulates cholesterol accumulation (Erin et al., 2015).

CXCR2

It is a GPCR (G-protein coupe receptor) that mediates in the chemotaxis and is known to play a key role in immune response including atherosclerosis by mediating in macrophage accumulation in lesion formation stage.CXCR2 is express in macrophage, monocytes and neutrophils and binds to several chemokine like IL-8 (CXCL8), Gro-α (CXCL1). Activation of this receptor promotes angiogenesis enhances the monocyte-endothelial adhesion by enhancing VEGF (Vascular endothelial growth factor) expression (Erin et al, 2015).

CYP1A1

It is known as cytochrome P450 1A1 and as referred as aryl hydrocarbon hydroxylase. When TCDD binds to AhR and migrates to nucleus its forms the heterodimer with the help of Aryl hydrocarbon nuclear translocator. CYP1A1 possess a DNA binding region known as Doxin response elements (DRE’s) and leads to changes in gene expression and signals for toxic and biochemical responses (Chang et al., 2012)

IL-8

It acts as a contributing factor for artherosclerosis as it palys a vital role in the pathogensis of vascular disease. IL-8 is affiliated to macrophages and in artheroclerotic tissue it leads to the induction of foam cells with oxidised LDL. In the present study it has shown that TDCC induces the expression of IL-8 and induces neutrophil against macrophage mediated inflammation in artherosclerosis.

INCB3344

It is  a CCR2 inhibitor and is an antagonist of CCR2 receptor and it induces the signal for kinase phosphorylation and chemotaxis by inhibiting CCL2 mediated functional responses.in the present study it has been shown that INCB3344 does not decrease the accumulation of alcohol.

MCP-1

Monocyte chemoattractant protein (MCP-1) is chemokine that is known to mediate the chemotaxis of monocytes. CCR-2 acts as a receptor for MCP-1 and in present study it has been shown that TCDD increase the expression of MCP-1 that decrease the expression of inflammatory genes.

ApoE-/-

MMP-12

It is an indicator of activated macrophages and foam cells and is a marker for foam cells. In the present study it has been shown that MMP-12 is involved in the progression of artherosclerosis in ApoE-/- mice.

MNF

It is an AhR anatagonist  and in the present study  it has shown that specific TCDD gene supress the expression of MNF hence it is not able to inhibit the expression of artherosclerotic lesion.

SB225002

It is a selective CXCR2 antagonist and prevents IL-8 dependent chemotaxis. In the present study it was found that SB225002 blocks CSE and TCDD induced cholesterol accumulation that reduces the formation of aortic plaque.

TCDD

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) activates the AhR induced inflammatory signals that leads to the formation of foam cells. In the present study the exact mechanism involved in artheroclerotic lesion formation was elucidated and was found that there was TCDD dependent progression of  atherosclerotic lesions in ApoE-/- mice.

U937

In the present study U937 was monocytic cell line which was used to assess the cell differentiation, small transient RNA transfection and it work as an in vitro model for cholesterol accumulation. 

VEGF       

It is a vascular endothelial growth factor which acts as a down-stream target for CCXCR2 as it is expressed after activation of chemokine that induces monocyte epithelial adhesion molecule and increase the expression of VEGF as signal for artherogenesis.    

Why was the above data set included in the paper? What does it demonstrate? What is scramble?  

The present result is expression of IL-8 and Ahr mRNA in U-937 cell after gene silencing. Total RNA was designed after post transfection (48 h) with either a scrambled siRNA or a specific siRNA targeted. Here scrambled RNA refers to the negative control. The result indicates that AhR induces vascular inflammation and stimulates IL-8 for the progression of artherosclerotic lesion

Bay 11-7082

It is known to prevent nuclear factor κβ (NF- κβ) by activating I κβ phosphorylation and inhibits ERK. In the present study it was demonstrated that TCDD stimulation for IL-1β depends upon the NF- κβ.

CCR2

It is a receptor for MCP-1 and mediates in monocyte chemotaxis and it contributes in the development of atherosclerosis plaques by AhR activation.

CXCR3

It is a receptor known to be present on synovial cells. In the present study it was used to semonstrate the level of AhR in synovial cells.

ERK

It is an extracellular receptor kinase and it is known to be involeved in AhR-TCDD mediated IL-1β  expression.

IL-6

In the present study TCDD stimulates the expression of IL-6 by binding to AhR and transmitted by NF-κβ and ERK signalling pathways.

IL-8

It is a cytokine produced by epithelial cells and macrophages. In the present study it was demonstrated that TCDD up-regulates the expression IL-8 in synocyte cells.

Infliximab

It is an anti TNF-α antibody and it abolishes the TNFα induced AhR expression.

MMP3

In the present study the expression MMP3 protein is upregulated following TCDD induced AhR activation.

NF κβ

It is nuclear factor that control the transcription of DNA. In the present study it was concluded that TCDD stimulates IL-1β is mediated by NFκβ and RRK signalling cascade.

α-NP

it is an nuclear protein that is vital in cell cycle progression.

TNF-α

It is a tumor necrotic factor which is majorly involve in inflammation and with involvement of several cytokine it forms acute phase reaction. In the present study it was reported that AhR  expression in synovial cell increases TNF-α expression (Evans et al,.2014).

U0126

It is an ERK pathway inhibitor and it decreases TCDD induced IL-1β expression in the sudy.

Correct description of data

Effect of GNF351 is in dose dependent manner as it down-regulates the expression of MMP-9 and MMP-2.

I found TNF-α as most challenging as it is the key player in regulating the inflammation not only in artherosclerosis but it is also involved in pollutant or metal induced oxidative stress and  been major contributes factor in various type of cancers.

References

Boring, L., Gosling, J., Cleary, M., Charo, I. F. (1998). Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature.394:894–897.

Chang, Y., Z., Lin, H. C., Chan, S. T., Yeh, S. L. (2012). Effects of quercetin metabolites on the enhancing effect of β-carotene on DNA damage and cytochrome P1A1/2 expression in benzo[a]pyrene-exposed A549 cells. Food Chemistry. 133(2):445-450

Erin, N., Nizam, E., Tanrıover, G., Koksoy, S. (2015). Autocrine control of MIP-2 secretion from metastatic breast cancer cells is mediated by CXCR2: a mechanism for possible resistance to CXCR2 antagonists. Breast Cancer Research and Treatment. (In press)

Evans, H. G., Roostalu, U., Walter, G. J., Gullick, N. J., Frederiksen, K. S., Roberts, C. A., Sumner, J., Baeten, D. L., Gerwien, J. G., Cope, A. P., Geissmann, F., Kirkham, B. W., Taams, L. S. (2014). TNF-α blockade induces IL-10 expression in human CD4+ T cells. Nature Communication. 5:3199

Kobayashi, S., Okamoto, H., Iwamoto, T., Toyama, Y., Tomatsu, T., Yamanaka, H., Momohara, S. (2008). A role for the aryl hydrocarbon receptor and the dioxin TCDD in rheumatoid arthritis. Rheumatology . 47(9):1317-22

Lahoti, T. S., Hughes, J. M., Kusnadi, A., John, K., Zhu, B., Murray, I. A., Gowda, K., Peters, J. M., Amin, S. G., Perdew, G. H. (2014). Aryl hydrocarbon receptor antagonism attenuates growth factor expression, proliferation, and migration in fibroblast-like synoviocytes from patients with rheumatoid arthritis. Journal of  Pharmacology Experiment and Therapy. 348(2):236-245

Wu, D., Nishimura, N., Kuo, V., Fiehn, O., Shahbaz, S., Van Winkle, L., Matsumura, F., Vogel, C. F. (2011). Activation of aryl hydrocarbon receptor induces vascular inflammation and promotes atherosclerosis in apolipoprotein E-/- mice.  Arteriosclerosis Thrombosis Vascular  Biology. 31(6):1260-1267