SOD3 and Renin Angiotensin System

 Medical foods do not require a prescription and are not regulated as drugs.  They may provide nutrition when the patient is too incapacitated to get said nutrition from a normal diet.  In this case we have a sick guy who just doesn’t feel like eating copper rich foods like liver and kale.  In this post we will cover how copper may play a role in the renin angiotensin system (RAS) that may be compromised in severe Covid-19 and other infections. 

What is the Renin Angiotensin System (RAS)?

Qin and coworkers (2020) first noted hypertension as a risk factor for severe versus mild forms of COVID-19.  Lippi and coauthors (March 31, 2020) summarized literature of numerous studies and found a consistent correlation between severe COVID-19 and hypertension.  Which came first?  Hypertension or Severe Covid-19?  Was hypertension pre-existing or the result of the infection?  Was pre-existing hypertension controlled by the use of an ACE inhibitor that might have increased the expression of the ACE2 enzyme/COVID-19 receptor?  Or was pre-existing hypertension controlled by use of  β-adrenergic receptor blockers, controlled by life style changes like low sodium diets, or left uncontrolled? Hao Cheng and colleagues of the Peking University First Hospital of Beijing reviewed risk factors or severe COVID-19 infections and the COVID-19 receptor angiotensin converting enzyme 2 (ACE2). ACE2 is a receptor for other corona viruses.  Let us take a closer look at the RAS.

SOD3_RAS_2
The angiotensin II converting enzyme 2 (ACE2) role in the renin-angiotensin-system (RAS). Cu/Zn superoxide dismutase (SOD) is a brake in the RAS.

 When blood flow to the kidney is decreased, plasma pro-renin is cleaved to the active protease renin. Renin cleaves angiotensinogen to angtiotensin I. Angiotensin converting enzyme (ACE) cleaves angiotensin I to angiotensin II. Angiotensin II binds to the angiotensin receptor 1 (AT1). The primary result is increased expression of NADPH oxidase, a super oxide generating enzyme. Superoxide reacts with with the vasodilator nitric oxide (NO) to produce peroxynitrite. Blood vessels constrict and renal blood flow is increased.

Cu/Zn SOD3 and RAS, a closer look

ACE2, aka the Covid-19 receptor, used to be primarily regarded as the first brake to the RAS.  Ozumi (2012) discovered a second brake: increased expression of Cu/Zn superoxide dismuase 3 (SOD3). Activation of the AT1 receptor might even stimulate Cu(I) uptake by the copper transporter Ctr1. Cu(I) is handed off to the Cu(I) chaperone Atox1, a transcription factor for the SOD3 gene. 

SOD3_RAS_3
Copper in the +1 oxidation is involved in several levels in producing Cu/Zn SOD3 (1) as acquired by Cu(I) channel Ctr1 (2 ) in chaperone/transcription factor Atox1, (4) in channel ATP7A that loads Cu in Golgi where SOD3 is being processed for secretion.

Multiple levels of regulation…

  • Sean Didion (2012) chose not to follow up on the Ozumi (2012) suggestion that ATR1 modulates the Ctr1 channel.  Didion focused on demonstrating that angiotensin II also increases protein levels of Atox1 and SOD3.
  • Meanwhile, Wang (2016) reported that SOD3 levels are decreased in the brains of ACE2 knock out mice. If anything, angiotensin II should increase SOD3 in these mice. It should be noted that both the MAS and AT1 receptors signal via heterotrimeric G-proteins.
  • Abouhashem (May 2020) isolated single cell RNA from alveolar type II epithelial cells.  These cells came from elderly and young donors.  The mRNA were sequenced and expression levels compared.   The rationale was taht colocalization of ACE2 and TMPRSS2 enables Covid-19 to invade cells. Expression levels of these genes in the alveolar type II cells of elderly and young patients were comparable.  In cells from the elderly, 263 genes were down regulated and 95 up regulated.   Superoxide dismutase 3 (SOD3) was identified as the top-ranked gene that was most down regulated in the elderly.  The authors proposed that SOD3 and the ATF4 transcription factor -related antioxidants will work in synergy with promising antiviral drugs such as remdesivir to further improve COVID-19 outcomes in the elderly.
  • Cheng (2020) discussed ACE2 as one means of applying the brake to the RAS increase in blood pressure. COVID-19 binding to ACE2 might compromise this brake. There is an internal feedback loop that involves Cu(I). One way or another, SOD3 expression is increased by angiotensin 1-7 and aginiotensin II (aka 1-8). A functional SOD3 enzyme requires repletion with copper in the +1 oxidation state.

In summary

To the invited guest reading this post, we are not making claims at this point.  We do want to remind you that the copper binding protein Atox1 regulates the expression of SOD3.  We do not know if these elderly volunteers were copper deficient compared to younger volunteers.

RAS, not just corona virus infections

The COVID-19 infection is just one example in which the RAS system might be activated: (1) decreased fluid intake due to compromised GI function that is not quite diarrhea and (2) direct activity of the virus on the RAS. Naturally healthcare professionals would be involved in assays involved with plasma SOD3 activity and copper content of ceruloplasmin.

But also bacterial infections

Bacterial sepsis involves SOD3. Constantino (2014) induced bacterial sepsis in a rat cecal ligation and preforation model. Cecal perforation would be akin to an appendicitis in humans. These authors found an increase in SOD3 levels following sepsis that were not able to totally prevent oxidative stress and inflammation associated with ONOO− production. While the rats should not have been copper deficient, the role of supplemental to replete the new production of SOD3 was not examined. Mechanism(s) of increased SOD3 were not examined, but one would expect activation of the RAS in response to the massive vascular collapse that is associated with sepsis. Human patients experiencing an appendicitis would not be boosting their serum copper via normal Cu(I) found in foods. Cu(I)NA2 administered as a medical food would have to be done under the supervision of a physician.

And also yeast infections

Candida (yeast ) infections offer another twist to SOD3 and Cu(I). Yeast express a zinc free, Cu only, superoxide dismuase (SOD5) that enables them to survive super oxide produced in the phagosomes of macrophage and neutrophils. SOD5 is an extracellular enzymes attached to the cell membrane by way of glyosylphosphatidylinositol linkages (Gleson 3015).

Unlike mammalian secreted SOD3, SOD5 does not use these Golgi proteins

  • the copper chaperone Atox1
  • copper-transporting ATPases

Gleason (2014) also proved that,  unlike intracellular mammalian SOD1, yeast SOD5 does not require

  • a CCS chaperone
  • Yeast acquires Cu(II) from the extracellular mileau of the host.

This  host source might be Cu(II) bound to albumin. Robinette (2020) compared the affinities yeast copper only SOD5 and bovine SOD1 for copper using Cu(II) chelators. They found that SOD1 has a higher affinity for Cu(II) than yeast SOD5. The right Cu(I) copper supplement may

  1. feed the patient’s SOD3 and SOD1
  2. while not feeding Cu(II) to SOD5 of the yeast pathogen.

The case for Mitosynergy’s cuprous nicotinate , Cu(I)NA2, as a “Medical Food” or a new drug

. It is proposed that Cu(I)NA2 is a way of obtaining copper in its +1 oxidation state for those who are too sick to eat the large amounts of copper rich foods to get said copper in its natural +1 oxidation state. Any infection, be it fungal, viral, or bacterial is associated with large production of the reactive oxygen species super oxide. 

Septic shock is also associated with vascular collapse and the associated activation of the Renin-Angiosystem-System.  Angiotnsin II has even been explored as a means of preventing vascular collapse and multi-organ failure (Corrêa  2015). 

As reviewed in this post, angiotensin II is also a way of boosting blood levels of Cu/Zn SOD3.  

No appetite or unable to eat copper containing foods

While Cu(I)NA2 has the same oxidation state as copper naturally occurring in the food we eat, it is a processed product to deliver required amounts of copper to patients who are too ill to large amounts of food. In the case of infections it is critical that enzymes such as superoxide dismutase are replete with the copper cofactor.

Feeling too sick to eat is a common symptom of many illnesses, not just infections. COVID-19’s affect on the GI tract may be under recognized according to a letter by Weicheng Liang and colleagues to the British Medical Journal Gut. These authors argued that while only a smaller fraction of COVID-19 patients had out right diarrhea, the small intestine might be compromised and the sight of COVID-19 infection due to the extensive GI expression of ACE2, the receptor for the COVID-19 spike glycoprotein.

Unable to eat

The appendicitis patient may be NPO, “nil per os”…. “nothing by mouth.”    A few arguments for non oral routes for drug status…

  1. No duodenum…  Griffith (2009) was one of the first to report copper deficiency secondary to the “roux-en-Y” gastric bypass that may takes the duodenum and 100-300 cm of the proximal jejunum. This is one of many papers addressing this particular problem.
  2. Absorption by the colon  Charlie Barker, owner and CEO of Mitosynergy, has talked of colonic andministration of Cu(I)NA2 via the rectal route. My big questions for gatroenterlogists would  (1) Are appendicitis patients NPO because Vagas nerve stimulation make the condition worse?  (2) Does injecting something into the patient’s colon via the rectum stimulate the Vagus nerve?
  3.  Cu+ transporters in the colon Here is an overview of the Cu(I) transporter Ctr1 offered by ProteinAtlas.org.  It become readily apparent from the brown antibody staining why gastric bypass patients may become copper deficient.
If colonic delivery of drugs, why not colonic delivery of CuI()? Ctr1 is expressed in the colon
Antibody staining against the Ctr1 Cu(I) transport protein failed to demonstrate expression in the oral mucosa and salivary gland. A small amount of expression was found in the esophagus and colon. Moderate expression was found in the duodenum. Nuclei are stained blue. Ctr1 stains brown.

Cu(I)NA2 already has clearance from the FDA as a new dietary ingredient. In an infection such as COVID-19 that can compromise the gastrointestinal tract, obtaining the proper dose may require medical supervision. This supervision may include

  • rectal administration bypassing the oral route
  • measuring the superoxide dismutase level in the patient’s blood
  • or the copper load in the Cu(I) carrier protein ceruloplasmin.

Additional information

References

Abouhashem AS, Singh K, Azzazy HME, Sen CK.  (2020) Is Low Alveolar Type II Cell SOD3 in the Lungs of Elderly Linked to the Observed Severity of COVID-19? Antioxid Redox Signal. 2020;10.1089/ars.2020.8111. Link

Cheng H, Wang Y, Wang GQ. (2020) Organ-protective Effect of Angiotensin-converting Enzyme 2 and its Effect on the Prognosis of COVID-19. J Med Virol. 2020 Mar 27. Review. Link

Constantino L, Gonçalves RC, Giombelli VR, Tomasi CD, Vuolo F, Kist LW, de Oliveira GM, Pasquali MA, Bogo MR, Mauad T, Horn A Jr, Melo KV, Fernandes C, Moreira JC, Ritter C, Dal-Pizzol F. (2014) Regulation of lung oxidative damage by endogenous superoxide dismutase in sepsis. Intensive Care Med Exp. 2014 Dec;2(1):17. Link

Corrêa TD, Takala J, Jakob SM.(2015)Angiotensin II in septic shock. Crit Care. 2015 Mar 16;19:98 Link

Didion SP.(2012) Antioxidant 1 in hypertension: more than just a copper chaperone. Hypertension. 60(2):285-7 Link

Gleason JE, Galaleldeen A, Peterson RL, Taylor AB, Holloway SP, Waninger-Saroni J, Cormack BP, Cabelli DE, Hart PJ, Culotta VC. (2014) Candida albicans SOD5 represents the prototype of an unprecedented class of Cu-only superoxide dismutases required for pathogen defense Proc Natl Acad Sci U S A. 111(16):5866-71. Link

Griffith DP, Liff DA, Ziegler TR, Esper GJ, Winton EF.(2009) Acquired copper deficiency: a potentially serious and preventable complication following gastric bypass surgery. Obesity (Silver Spring).17(4):827-31. Link

Liang W, Feng Z, Rao S, Xiao C, Xue X, Lin Z, Zhang Q, Qi W. (2020) Diarrhoea may be underestimated: a missing link in 2019 novel coronavirus. Gut. 2020 Feb 26. pii: gutjnl-2020-320832. Link

Lippi G, Wong J, Henry BM.(2020) Hypertension and its severity or mortality in Coronavirus Disease 2019 (COVID-19): a pooled analysis. Pol Arch Intern Med. 2020 Mar 31. Link

Meng J, Xiao G, Zhang J, He X, Ou M, Bi J, Yang R, Di W, Wang Z, Li Z, Gao H, Liu L, Zhang G. (2020)Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. Emerg Microbes Infect. 9(1):757-760. Link

Ozumi K, Sudhahar V, Kim HW, Chen GF, Kohno T, Finney L, Vogt S, McKinney RD, Ushio-Fukai M, Fukai T. (2012) Role of copper transport protein antioxidant 1 in angiotensin II-induced hypertension: a key regulator of extracellular superoxide dismutase.Hypertension. 60(2):476-86. Link

Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, Xie C, Ma K, Shang K, Wang W, Tian DS. (2020) Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis. 2020 Mar 12. pii: ciaa248.

Robinett NG, Culbertson EM, Peterson RL, Sanchez H, Andes DR, Nett JE, Culotta VC. (2019) Exploiting the vulnerable active site of a copper-only superoxide dismutase to disrupt fungal pathogenesis. J Biol Chem. 294(8):2700-2713 Link

Wang XL, Iwanami J, Min LJ, Tsukuda K, Nakaoka H, Bai HY, Shan BS, Kan-No H, Kukida M, Chisaka T, Yamauchi T, Higaki A, Mogi M, Horiuchi M. (2016) Deficiency of angiotensin-converting enzyme 2 causes deterioration of cognitive function. NPJ Aging Mech Dis. 2016 Oct 20;2:16024. Link

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