Missing Link? Endothelin1 high in pwMS

A forum to discuss Chronic Cerebrospinal Venous Insufficiency and its relationship to Multiple Sclerosis.

Re: Missing Link? Endothelin1 high in pwMS

Postby cheerleader » Sun Mar 24, 2013 12:27 pm

Cece wrote:Treatment of stenoses leads to reduction in ET-1.
http://www.ncbi.nlm.nih.gov/pubmed/21677436 (renal artery stenosis)
http://www.ncbi.nlm.nih.gov/pubmed/11137092 (carotid artery endoarterectomy surgery)
If CCSVI venoplasty is successful, ET-1 might become normalized.
Very interesting about the zinc and magnesium, I did not know they had an effect on ET-1!!


great papers, Cece!
Dr. Cooke talks about how shear stress eventually lowers ET-1. Good blood flow heals the endothelium. A virtuous cycle!
Physiologic levels of flow tend to inhibit the release of endothelin-1 (0285,0290,0295,0300,0305), a potent peptide vasoconstrictor. The release of endothelin-1 is known to be inhibited by NO (0310). However, the effect of shear stress on the release of endothelin-1 from endothelial cells is complex. Physiologic levels of shear stress induce a transient increase in endothelin-1 messenger ribonucleic acid (mRNA) expression and peptide release, which is followed by a significant suppression ((0295),(0305),0315). In human umbilical vein endothelial cells, low levels of shear stress stimulate the release of endothelin-1, whereas high levels inhibit its release (0285).

http://content.onlinejacc.org/article.a ... id=1121490
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Re: Missing Link? Endothelin1 high in pwMS

Postby gibbledygook » Sun Apr 07, 2013 2:50 am

salvia miltiorrhiza is great for lowering endothelin - 1.

Biochim Biophys Acta. 2006 Jan;1760(1):1-9. Epub 2005 Oct 3.
Cryptotanshinone inhibits endothelin-1 expression and stimulates nitric oxide production in human vascular endothelial cells.
Zhou Z, Wang SQ, Liu Y, Miao AD.
Source
Laboratory of Biotechnology, Beijing Institute of Radiation Medicine, Taiping road 27#, Haidian district, Beijing 100850, PR China.
Abstract
The Chinese herb Salvia miltiorrhiza (SM) has been found to have beneficial effects on the circulatory system. In the present study, we investigated the effects of cryptotanshinone (derived from SM) on endothelin-1 (ET-1) expression in human umbilical vein endothelial cells (HUVECs). The effect of cryptotanshinone on nitric oxide (NO) in HUVECs was also examined. We found that cryptotanshinone inhibited basal and tumor necrosis factor-alpha (TNF-alpha) stimulated ET-1 secretion in a concentration-dependent manner. Cryptotanshinone also induced a concentration-dependent decrease in ET-1 mRNA expression. Cryptotanshinone increased basal and TNF-alpha-attenuated NO production in a dose-dependent fashion. Cryptotanshinone induced a concentration-dependent increase in endothelial nitric oxide synthase (eNOS) expression without significantly changing neuronal nitric oxide synthase (nNOS) expression in HUVECs in the presence or absence of TNF-alpha. NOS activities in the HUVECs were also induced by cryptotanshinone. Furthermore, decreased ET-1 expression in response to cryptotanshinone was not antagonized by the NOS inhibitor l-NAME. A gel shift assay further showed that TNF-alpha-induced Nuclear Factor-kappaB (NF-kappaB) activity was significantly reduced by cryptotanshinone. These data suggest that cryptotanshinone inhibits ET-1 production, at least in part, through a mechanism that involves NF-kappaB but not NO production.
PMID: 16289876 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/16289876
3 years antibiotics, 06/09 bilateral jug stents at C1, 05/11 ballooning of both jug valves, 07/12 stenting of renal vein, azygos & jug valve ballooning,
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Re: Missing Link? Endothelin1 high in pwMS

Postby NZer1 » Sun Apr 07, 2013 11:57 pm

I have just caught up, gasp, what an amazing thread! Great work! :)

Questions,

Is it an injury to the vein that creates production of excessive Endothelin-1 or is it purely something that PwMS are noted as having ?

If 'normals' have injury/infection/inflammation to the veins then are they in a situation of over production of Endothelin-1 and what is the outcome, why are PwMS different?

If pain is one of the side effects of overproduction of Endothelin-1 is this going to be common in de-generative disease across the board?

Is Endothelin-1 and CCSVI inter linked or is it only the reflux/back jets creating lesions which is the cause of the 224% Endothelin-1 level in MS?

If diet and lifestyle (Leaky Gut) are out of 'balance' then will vascular health issues such as wall damage from infections also produce high Endothelin-1 which Dr Simka has just suggested in his paper?

Things seem to be connecting!

Great finds and sharing, thank you everyone!
:)
Nigel

I have sent a message to Franz Schelling, I hope he will comment as well!
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Re: Missing Link? Endothelin1 high in pwMS

Postby NZer1 » Mon Apr 08, 2013 12:29 am

Left field thought,

Is the pain in Varicose Veins caused by the Endothelin-1 increase from the vein damage?

What is the level of Endothelin-1 in patients with Varicose veins?
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Re: Missing Link? Endothelin1 high in pwMS

Postby NZer1 » Mon Apr 08, 2013 12:50 pm

Over night feed back from Franz Schelling;
Franz Schelling, Venous blood pushed into the venous periphery causes increased shear stress not only for endothelial cells but also all blood cells. Effects of this enhanced tear and wear have early been made evident in a reduced osmotic resistance of the red blood corpuscles. Expecting drugs improving the condition of blood and endothelial cells in multiple sclerosis might halt the disease process seems not all to well founded an idea.

And
Franz Schelling, The peripheral impact of venous blood being demonstrated by the emergence of Dawson's fingers causes not only an intensified shear stress on the involved endothelial cells but also on the blood cells.

My reply,
Nigel Wadham, Thanks Franz Schelling I think this gives a tool for defining what is MS! Understanding the processes and the additional compounding effect will give insights to symptom causation imo.
A finding like this must be a major point of focus and then comparing to other diseases such as Alzheimers, Dementia etc will create more depth of understanding than Mouse Models and Auto-immune time wasting theories! ;)

Regards,
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Re: Missing Link? Endothelin1 high in pwMS

Postby cheerleader » Mon Apr 08, 2013 1:11 pm

Just want to clarify a bit on Dr. Schelling's response, Nigel.
Shear stress, when it is laminar, is a good thing. It enhances NO and keeps vessels open and flowing, and maintains normal coagulation. It is essential for endothelial cell survival.

It is turbulant, disturbed, refluxive flow which is detrimental---which is Dr. Schelling's point with his Dawson's Fingers reference. Dawson's Fingers are related to this reversal of flow, or disturbed shear stress. Might be a language discrepancy, where he says "intensified shear stress" meaning turbulant.


Finally, shear stress may be critical for endothelial cell survival. Early studies performed by Davies et al12 demonstrated increased endothelial cell turnover in areas that experience turbulent shear stress conditions, suggesting compromised endothelial cell integrity under these conditions. Several recent studies report that the lack of shear stress triggers apoptosis in endothelial cells.53 54 Other investigators have demonstrated that shear stress is required for optimal regeneration of an injured endothelium. Vyalov et al55 reported that under low shear stress conditions, endothelial cells on the border of a wound edge failed to maintain contact with neighboring cells and were oriented randomly. Further, the cells spread and migrated into wound sites more slowly. While steady shear seems to be necessary for endothelial cell integrity, several investigators have demonstrated that steady shear inhibits proliferation of cultured endothelial cells.56 Thus, it appears that shear stress acts as an endothelial cell “survival” factor rather than as a “growth” factor.

http://atvb.ahajournals.org/content/18/5/677.long

hope that explains his comment a bit better--
cheer
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
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Re: Missing Link? Endothelin1 high in pwMS

Postby Cece » Mon Apr 08, 2013 3:03 pm

Thank you both for the explanation and, Nigel, for getting us Dr. Schelling's insights.
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Re: Missing Link? Endothelin1 high in pwMS

Postby cheerleader » Mon Apr 08, 2013 4:16 pm

NZer1 wrote:Left field thought,
What is the level of Endothelin-1 in patients with Varicose veins?


Plasma levels of Endothelin 1 is elevated in varicose veins. Great question, Nigel. Another thing people with venous disease and people with MS share---

Plasma ET-1 concentration was higher in varicose than in normal saphenous veins (4 +/- 0.1 pmol/L vs 2.6 +/- 0.1 pmol/L, P < 0.001), and it significantly increased (P < 0.001) in both groups after venous stasis when compared with baseline (6.8 +/- 0.9 pmol/L and 3.6 +/- 0.1 pmol/L in varicose and normal saphenous veins, respectively). Absolute increase in plasma ET-1 was significantly greater in varicose than in normal saphenous veins (2.8 +/- 0.9 pmol/L vs 1.0 +/- 0.2 pmol/L, P < 0.01). In conclusion, increased local ET-1 release in varicose saphenous veins could be a marker for venous endothelial activation/damage and/or contribute to promote the morphologic alterations of the varicose vein wall by stimulating smooth muscle cell proliferation.

http://www.ncbi.nlm.nih.gov/pubmed/9313626
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
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Re: Missing Link? Endothelin1 high in pwMS

Postby NZer1 » Mon Apr 08, 2013 5:57 pm

Left outer field question then,

If there is a vascular infection such as CPn, a known intracellular infecter (Stratton found 98% of autopsy MS brains with CPn antigens and infections) of both macrophages and venous tissue what is going to happen to the EN-1 level and will there be a disease expression, such as MS?

I spoke with Paul Thibault and he has been researching this for a while, as well as his seemingly endless back load of patients since the Catalyst program! http://www.youtube.com/watch?v=EpMvDe8-qsM

;)
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Re: Missing Link? Endothelin1 high in pwMS

Postby NZer1 » Tue Apr 09, 2013 12:46 pm

Feedback from Paul Thibault ;
" Once one gets into cellular biology, everything gets a lot more complex. This is a rather brief report published some time ago and doesn't appear to have been followed up with further research to develop the pathogenesis in this direction. I am currently planning research in a slightly different direction that will hopefully fill in one of the major gaps in the infective venulitis theory. I may be able to post several of the past research articles that give some pointer to the area we are looking at."

Is it interesting that the 224% in MS versus normal finding has only interested a few?

Dr S doesn't see it as a 'smoking gun' and looks forward to more info.

;)
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Re:

Postby cheerleader » Tue Apr 09, 2013 1:52 pm

Nigel- I saw the issue when Jeff was dx, and tried to explain it best I could. I hope researchers will continue to explore the connection. I know they are looking at microparticles at LSU, that's where I first read about this information. Infections are listed in the endothelial health program as contributors to dysfunction. They may be an issue for some, not all. I think that's why Dr. S and others are waiting for more research. Dr. Cooke continues to explore the connection to modern lifestyle---high ET 1 is not just about infections.
cheerleader wrote:
An over-expression of endothelin-1 can be linked to genetics, it can be caused by diabetes, or induced by hypoxic injury. It is linked to obesity, high fat diets, infections, inflammation and modern life.

When I started looking at Jeff's serum numbers at diagnosis (high coagulation, high liver enzymes) and his physical issues (jaundice, petechiae) I kept coming back to endothelial dysfunction. That's when I started trying to find out how to balance nitric oxide and calm down this response of hypercoagulation and vasoconstriction.

Weight loss reduces endothelin 1
http://www.ncbi.nlm.nih.gov/pubmed/16741046
Exercise
http://jap.physiology.org/content/95/1/336.abstract
and I wrote up the program for Jeff:
http://www.ccsvi.org/index.php/helping- ... ial-health
Zinc is in the program, so are antioxidants, sunshine, laughter, exercise, low fats, proteolytic enzymes, EGCG, quercetin, bromelain, and lots of other stuff. It's all in the program.

The good news is that even if you are predisposed to high endothelin 1 overexpression, there is much you can do with diet and lifestyle and supplements to counteract this. It can be reversed. Of course, I believe good flow and a reversal of disturbance and turbulant blood flow will help, which is why angioplasty for venous malformations is important. But much can be done with diet and lifestyle.

It baffles the mind how ET-1 levels could be 224% higher in pwMS, yet the connection to the vascular system is overlooked.
http://www.ncbi.nlm.nih.gov/pubmed/11315981
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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Re: Missing Link? Endothelin1 high in pwMS

Postby NZer1 » Tue Apr 09, 2013 2:34 pm

Thanks Joan I have ordered Doc Cooke's book and waiting.

I always look at things as WHY and the reason for high "Endothelin-1, a smooth muscle mitogen" occurring has my total attention.

It is interesting that there hasn't been further research looking at the incidence and coming to an understanding.

The other aspect is that there is a stand off between researchers regarding the causation of arteriosclerosis, one camp saying it is bacterially caused and the other flapping in the wind saying no it isn't! Yet the research is showing that treating with ABx protocols stops the progression of it! So there seems to be the same division in research across the board and that is why the Stealth Infection work of Prof Nicolson and others is falling on deaf ears. Bec Miller is providing a big push across the ditch in Australia regarding this and it has my attention as well. Many other Specialists that Bec has interviewed are connecting the dots Internationally. So what I am saying is that the diseases implicated eg atherosclerosis and also RA are also on the list for CPn infection incidence which for me is too 'interesting' to pass by.

I'm not saying that the 'standard' diseases implicated 'are the reason for MS/CCSVI/de-generative diseases', what I do see is that they play an active role in the jigsaw, and so does your list and the injury and spinal alignment collective. Some of us like me have the lot and have this thing called MS! A singular approach to treating only one of the factors is not going to protect against the disease as you have found with Jeff's multifaceted treatment program.
For me I have a raft of things to attend to and also keep an open mind as I hear about the scenarios of others, such as Marie and Mark Stecker who have been able to cross off some of the package or list of co-incidents as technology proves 'beyond doubt' that these issues eg Bacterial Infection are not an issue, or is it?
I am of course challenged deeply that technology isn't able to give better than a 60% reliable antigen test for Lyme or CPn involvement, so are Marie and Marc clear, or are they in a situation where the previous 'drugs' and Lifestyle/diet used enabled the bacteria to adapt their DNA and become even more of a Stealth risk in the equation? Monocytes and Marcophages still being hosts to the intracellular bacteria and spreading the bacterial Farmlets around the body still?

And that is why I look at this Endothelin-1, a smooth muscle mitogen as a new incidence factor to understand in depth and from all perspectives.

;)
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Re: Missing Link? Endothelin1 high in pwMS

Postby NZer1 » Tue Apr 09, 2013 3:52 pm

It seems that atherosclerosis is one of the few diseases that have generated interest in ET-1 , so does that mean the MS level is somehow related to atherosclerosis (a known bacterial disease) that is a vascular disease? (" inflammation of the vessel wall is a hallmark of atherosclerosis")

http://link.springer.com/article/10.1007/s003950050170
Abstract
The potent vasoconstrictor peptide endothelin-1 (ET-1) has been implicated in the pathophysiology of atherosclerosis and ist complications. Since inflammation of the vessel wall is a hallmark of atherosclerosis, the purpose of the present study was to investigate the influence of ET-1 on cytokine production in human vascular smooth muscle cells (SMC) as a marker of inflammatory cell activation. ET-1 (100 pM – 1 μM) stimulated interleukin-6 (IL-6) secretion from human vascular SMC in a concentration-dependent manner. The ET-A-receptor antagonist BQ-123 (10 μM), but not the ET-B-receptor antagonist BQ-788, inhibited IL-6 release. ET-1 also transiently increased IL-6 mRNA compatible with regulation of IL-6 release at the pretranslational level. Electrophoretic mobility shift assays demonstrated time-and concentration-dependent activation of the proinflammatory transcription factor nuclear factor-κB (NF-κB) in ET-1-stimulated human vascular SMC. A decoy oligodeoxynucleotide bearing the NF-κB binding site inhibited ET-1-stimulated IL-6 release to a great extent suggesting that this transcription factor plays a key role for cytokine production elicited by ET-1. Moreover, the antioxidant pyrrolidine dithiocarbamate (10 μM) inhibited ET-1-induced IL-6 release indicating involvement of reactive oxygen species in ET-1 signaling. ET-1-stimulated IL-6 secretion was also suppressed by diphenylene iodonium (40 μM), an inhibitor of flavon-containing enzymes such as NADH/NADPH oxidase. The results demonstrate the ability of ET-1 to induce an inflammatory response in human vascular SMC. These observations may contribute to a better understanding of the role of ET-1 in inflammatory activation of the vessel wall during atherogenesis.

Gards,
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Re: Missing Link? Endothelin1 high in pwMS

Postby NZer1 » Tue Apr 09, 2013 4:05 pm

"Weight loss reduces endothelin 1
http://www.ncbi.nlm.nih.gov/pubmed/16741046
We conclude that weight loss by low-calorie diet (i.e., lifestyle modification) reduces plasma ET-1 concentration in obese individuals. This reduction may contribute to the improvement of obesity-induced endothelial dysfunction."
My thinking is that the flow of blood and the inflammation from the athersclerosis aka CPn infection was 'changed' by the diet, which a known management tool for CPn infection.

"Exercise
http://jap.physiology.org/content/95/1/336.abstract"

My thinking is that blood stagnation or slow flows are the issue with the readings and that MS is potentially classed as stagnating blood from slow drainage of the brain, plus of course decreased activity. The underlying cause of the level is likely to be atherosclerosis and the exercise is improving the effect of the inflammation and infection.

;)
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Re: Missing Link? Endothelin1 high in pwMS

Postby NZer1 » Tue Apr 09, 2013 4:32 pm

When Endothelin-1 crosses the BBB due to the Franz Schelling back jets, entering the brain tissue from the pumping action and travelling through the Dawsons Fingers lesions what will the symptoms be I wonder?

Just asking, ;)
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