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New discovery in POTS (and possible reversal of epigenetic origin)

Belbyr

Senior Member
Messages
602
Location
Memphis
I know this is a CFS/ME board, but this is interesting considering a lot of CFS patients have autonomic problems. Some of you may be able to make more sense of this than myself.

The findings:
https://insight.jci.org/articles/view/90183

Easy to understand version:
Australian researchers have an exciting new study out on epigenetic findings in POTS. It's very complicated, but here's a plain English version of their findings. NET is a gene that makes the norepinephrine transporter (NET) protein. This protein helps our autonomic nerves recycle norepineprhine, a substance that nerves use to send messages to each other. When there aren't enough NET proteins made, less norepineprhine is recycled, and more of it is spilled over into the bloodstream. This increases the overall tone of the sympathetic nervous system, which can lead to POTS like symptoms or can worsen them.

The Australian researchers found that the NET gene is being "silenced" (not making enough NET protein) in some POTS patients. The study included 9 POTS patients.

The researchers believe this "silencing" is happening because of a complex epigenetic mechanism. Epigenetic refers to factors that regulate gene expression without an alternation in the gene itself.

The researchers took white blood cells from POTS patients, which had reduced NET protein, and treated the cells with vorinostat, a medication known to reverse the epigenetic mechanism that was found. When the white blood cells from POTS patients were treated with vorinostat, the NET protein level increased, suggesting that the epigenetic mechanism is treatable!

Please don't rush out and try to get yourself a dose of vorinostat. It's a serious drug used to treat lymphoma that can cause some pretty bad side effects, and we don't yet know how it would work in POTS patients, if at all. There may be other drugs or non-pharmacological treatments that can reverse the epigenetic mechanism too.

We have hope that this will lead to more research, and perhaps new treatment options for a subset or all POTS patients someday.

Speaking of more research... if you've read this far down, we'd like to fill you in on a secret. We're planning an NET epigenetic study for the 2017 annual conference with researchers at three major autonomic labs, because we need NET epigenetic data on a larger group of patients. Details to be posted soon! #ResearchMeansHope
 

Lolo

Senior Member
Messages
306
Location
AUS
I am in Australia and the last doctor I went to (January this year) had never heard of POTS. I suspect I have OI.
And if I was was diagnosed with it I would also rather take supplements or less dangerous drugs.
 
Messages
86
When I went into hospital a few years ago displaying severe POTS symptoms upon sitting up/movement no one had a clue what was wrong, they did an ECG, decided my heart was fine and told me I was just stressed. Even the consultant cardio said that. Its scary really, for the 21st centuary. There is a real lack of knowledge about so called functional disorders and it's quite shocking that someone can have such severe symptoms and still be believed to be fine.
 

Belbyr

Senior Member
Messages
602
Location
Memphis
Any suggestions of supplements or less dangerous drugs we can discuss with our Dr's? If more comfortable you can PM me.

Thanks

This was pulled from dysautonomia international, I have no clue of any supplements. I know it is a small study, but this seems to fit the theory that is being applied to CFS/ME. Genetic issue(switch flipped)--->autoimmunity--->mitochondria dysfunction.
 

Sushi

Moderation Resource Albuquerque
Messages
19,935
Location
Albuquerque
NET is a gene that makes the norepinephrine transporter (NET) protein. This protein helps our autonomic nerves recycle norepineprhine, a substance that nerves use to send messages to each other.
Vanderbilt has been looking at NET for years but I don't know if their research included the epigenetics aspects. They knew that NET was important though. I wonder where they are with it now?
 

aaron_c

Senior Member
Messages
691
Thinking out loud:

Vorinostat is a histone deacetylase inhibitor, meaning that it stops a protein from taking acetyl groups off of DNA. I wonder if this means that B5 might be moderately helpful, as it is the backbone of the "CoA" in "Acetyl CoA"? Acetyl CoA, of course, is our body's (only I think?) acetyl group donor. Come to think of it anything that improves metabolism should help a little, as Acetyl CoA is produced from glycolysis, the beta-oxidation of fatty acids, the degradation of branch-chain ketogenic amino acids, and even acetate and ATP.

Of course, this stuff would only help to the degree that deficient NET is the problem, and also to the degree that there isn't something else inhibiting NET synthesis, or encouraging NET degradation.
 

Belbyr

Senior Member
Messages
602
Location
Memphis
Vanderbilt has been looking at NET for years but I don't know if their research included the epigenetics aspects. They knew that NET was important though. I wonder where they are with it now?

I believe they found a NET problem but it was only found in 1 patient or something like that... I think this is a little different. Satish Raj will be speaking at the DI conference in about 3-4 months. I'm sure this topic will come up.
 

Jenny TipsforME

Senior Member
Messages
1,184
Location
Bristol
Vorinostat can be used to reactivate latent viruses (probably not brilliant for ME!). Would this be intrinsic to what is making it useful for POTS or would alternatives not be immune system related?

It is definitely promising that they're getting to turn off the underlying mechanism behind POTS. I'm on bisoprolol and ivabradine to turn down symptoms but these aren't getting to the root cause.

I also think POTS really aggravates my ME in a vicious cycle, so atm may be best target for improving my overall health. Hopeful :)
 

Jenny TipsforME

Senior Member
Messages
1,184
Location
Bristol
Does anyone understand this?
J Cancer Res Clin Oncol. 2016 Feb;142(2):379-87. doi: 10.1007/s00432-015-2026-y. Epub 2015 Aug 28.
Vorinostat, a histone deacetylase (HDAC) inhibitor, promotes cell cycle arrest and re-sensitizes rituximab- and chemo-resistant lymphoma cells to chemotherapy agents.
Xue K1,2, Gu JJ3, Zhang Q1,2, Mavis C3, Hernandez-Ilizaliturri FJ3, Czuczman MS3, Guo Y4,5.
Author information

Abstract
PURPOSE:
Preclinical models of chemotherapy resistance and clinical observations derived from the prospective multicenter phase III collaborative trial in relapsed aggressive lymphoma (CORAL) study demonstrated that primary refractory/relapsed B cell diffuse large B cell lymphoma has a poor clinical outcome with current available second-line treatments. Preclinically, we found that rituximab resistance is associated with a deregulation on the mitochondrial potential rendering lymphoma cells resistant to chemotherapy-induced apoptotic stimuli. There is a dire need to develop agents capable to execute alternative pathways of cell death in an attempt to overcome chemotherapy resistance. Posttranscriptional histone modification plays an important role in regulating gene transcription and is altered by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDACs regulate several key cellular functions, including cell proliferation, cell cycle, apoptosis, angiogenesis, migration, antigen presentation, and/or immune regulation. Given their influence in multiple regulatory pathways, HDAC inhibition is an attractive strategy to evaluate its anti-proliferation activity in cancer cells. To this end, we studied the anti-proliferation activity and mechanisms of action of suberoylanilide hydroxamic acid (SAHA, vorinostat) in rituximab-chemotherapy-resistant preclinical models.

METHODS:
A panel of rituximab-chemotherapy-sensitive (RSCL) and rituximab-chemotherapy-resistant cell lines (RRCL) and primary tumor cells isolated from relapsed/refractory B cell lymphoma patients were exposed to escalating doses of vorinostat. Changes in mitochondrial potential, ATP synthesis, and cell cycle distribution were determined by Alamar blue reduction, Titer-Glo luminescent assays, and flow cytometric, respectively. Protein lysates were isolated from vorinostat-exposed cells, and changes in members of Bcl-2 family, cell cycle regulatory proteins, and the acetylation status of histone H3 were evaluated by Western blotting. Finally, cell lines were pre-exposed to vorinostat for 48 h and subsequently exposed to several chemotherapy agents (cisplatin, etoposide, or gemcitabine); changes in cell viability were determined by CellTiter-Glo(®) luminescence assay (Promega, Fitchburg, WI), and synergistic activity was evaluated using the CalcuSyn software.

RESULTS:
Vorinostat induced dose-dependent cell death in RRCL and in primary tumor cells. In addition, in vitro exposure of RRCL to vorinostat resulted in an increase in p21 and acetylation of histone H3 leading to G1 cell cycle arrest. Vorinostat exposure resulted in apoptosis in RSCL cell lines but not in RRCL. This finding suggests that in RRCL, vorinostat induces cell death by alternative pathways (i.e., irreversible cell cycle arrest). Of interest, vorinostat was found to reverse acquired chemotherapy resistance in RRCL.

CONCLUSIONS:
Our data suggest that vorinostat is active in RRCL with a known defective apoptotic machinery, it can active alternative cell death pathways. Given the multiple pathways affected by HDAC inhibition, vorinostat can potentially be used to overcome acquired resistant to chemotherapy in aggressive B cell lymphoma.
I thought the Rituximab and vorinostat link was interesting but I definitely don't comprehend this abstract.
 

Hip

Senior Member
Messages
17,824
Very interesting, @Belbyr

Wouldn't NET involvement depend on the POTS subtype though, with NET deficiency perhaps relating more to the low flow POTS (similar to the hyperadrenergic POTS)?

In low flow POTS, I read on the DINET forum here that there are two forms, one of which involves NET deficiency:

• Elevated angiotensin II (almost always exclusively female).
• Norepinephrine transporter (NET) deficiency (more equal in terms of sexes).
 

Belbyr

Senior Member
Messages
602
Location
Memphis
Yeah, I really have no idea honestly what the differences are of low flow and high flow POTS. I think there has been so many terms created within the POTS that specialists are now saying is not as big of a deal as once believed.

Vanderbilt thinks hyperadrenergic, hypovolemic, and neuro pots are most likely evident in most if not all cases of POTS after other diseases are ruled out.