I have found that a high proportion of chronic fatigue syndrome sufferers have mild to moderate elevations in circulating ACE levels. There is no evidence of pulmonary sarcoidosis. Macrophage abnormalities have not been reported in this setting (as far as I know), but circulatory changes and Orthostatic Hypotension have been. Low blood volumes and reduced cardiac indices have been reported and confirmed. Cytokine abnormalities, increased after exercise may be relevant. My theory is developing, and suggests NF-kB activation, suppressible by Vitamin D and DHEA supplementation, as evidenced by considerable falls in elevated serum ferritin levels, as a Type 1 Acute Phase Response, supporting the possible involvement of chronic TNF-alpha/IL-1b elevations in the circulation or from Kuppfer cells in close proximity to the liver, in these patients. I am trying to unify this concept by identifying a plausible explanation for the above mentioned long term serum ACE LEVELS.
Article Shedding the load of hypertension: The proteolytic processin...
I have no personal experience in this field. Nevertheless, in my opinion your point of view may be proper. Sincerely greetings, Zofia I. Niemir
Sheddases for ACE are ADAM family members like ADAM17 or possibly ADAM 10 or 12. The ADAMs also release TNF, and other cytokines plus their receptors. I don't know of any regulation of ADAMs by cytokines, but things like LPS, PMA and ionophores activate ADAM activities. In contrast, ADAM members directly affect cytokines signalling and processing of cytokines receptors and cytokines themselves ( the ones that are type I and II interval membrane proteins. Adam members release receptors that affect signaling in two ways. First, the receptor is no longer on the cell to carry out signalling events. second, the soluble receptors act to bind to the cytokines and neutralize then. I would not be surprised though if cytokines binding to receptors also regulates ADAM expression.
I think your theoy fits well with the notion that there is an increase in ADAM activity with inflammation. Lots of factors increase TACE and ADAM10 activity. The increase in these activities affect things thorough NFkB also by regulating receptor tyrosine kinase levels. There is a paper by Dan Conrad on NFkB and ADAM10 regulation. Just google Dan. TNf and IL1b transcription levels are affected by an inhibitor of ADAM 10.
So if you have more ADAM activity, maybe even ADAM12, for example, more ACE gets shed because of the increase in ADAM activity due to inflammation. PS, I think There is also a paper or two on VitD and VitA suppressing ADAM activity.
Dear Marcia Moss, thank you for your very interesting and informative answer (sorry for my delay in replying). I will follow up on your ideas. They may well resolve the question I am seeking to understand.
Warm regards,
John
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