ACE2 Receptor Science
Article by Stefan Burns - Updated November 2021. Join the Wild Free Organic email newsletter!
The Angiotension Converting Enzyme 2 (ACE2) receptor is a glycoprotein that is part of the renin-angiotensin-aldosterone system (RAAS). The RAAS system is a coordinated hormonal cascade which links together the cardiovascular, renal (kidney), gut, and adrenal systems, governing fluid and electrolyte balance and arterial pressure. ACE2 receptors are almost exclusively found in the kidneys, heart muscle, testis, small intestine, colon, and thyroid gland. Certain viruses bind to the ACE2 receptor found in cell membranes in order to gain entry into the cell for reproduction, the most notable virus which does this being SARS-CoV-2. Understanding the functions of ACE2 sheds light on how its dysregulation either by SARS-CoV-2 and fractions, or by other factors, can have such devastating impacts on health.
In this article we examine the main components of the RAAS system and discuss how they function in plain English. Afterwards the impact SARS-CoV-2 and its fractions has on the RAAS system is examined.
RAAS system
Renin-Angiotensin-Aldosterone System (RAAS)
The RAAS system has widespread biologic effects, being a critical regulator of blood volume, blood pressure, sodium reabsorption, inflammation, and fibrosis. RAAS is an important physiological regulator not only through the endocrine pathways but also at the local tissue level via a self-contained paracrine (cell to cell signaling) and autocrine (cellular self signaling) system.
Renin
Renin is a glycoprotein enzyme which cleaves angiotensinogen (AGT) into ANG I.
The enzyme renin is secreted by the kidneys in response to three stimuli:
A decrease in arterial blood pressure.
A decrease in sodium load as measured by the kidneys.
Sympathetic nervous system (fight or flight) activity, which also controls blood pressure.
The renin enzyme circulates in the bloodstream and hydrolyzes (breaks down) angiotensinogen (AGT) secreted from the liver into the peptide angiotensin I (ANG I).
Angiotensinogen (AGT)
The majority of AGT is synthesized in the liver in response to lowered blood pressure and secreted into the bloodstream. AGT is also synthesized in heart, vasculature, kidney, and adipose tissue. AGT is inactive and the only known precursor protein for angiotension peptides (ANG I, ANG1-7, ANG II, ANG1-9, etc), which are produced by successive enzyme cleavages.
Angiotensin (ANG I)
Angiotensin (ANG I) appears to have no direct biological activity and exists solely as a precursor to other angiotensin peptides.
Angiotensin II (ANG II)
ANG II is created from ANG I by ACE receptors. Unlike ANG I, ANG II is biologically active and causes vasoconstriction and an increase in blood pressure. ANG II acts on the adrenal cortex, causing it to release aldosterone, a hormone that causes the kidneys to retain sodium and lose potassium.
The multiple direct intrarenal actions of ANG II include renal vasoconstriction, tubular sodium reabsorption, tubuloglomerular feedback sensitivity, and modulation of pressure-natriuresis. The net results of ANG II’s many effects on the renal vascular and tubular systems is to decrease sodium excretion.
Cardiac interstitial fluid concentrations of ANG I and ANG II are over 100-fold those of plasma. The majority of ANG II in cardiac tissue is derived from myocardial synthesis of ANG I and not from uptake into the heart from the systemic circulation. The reason for this is because it is supremely important for the heart to be able to regulate its own pressure systems.
Aldosterone
Aldosterone plays an important part in cardiovascular health. Aldosterone is produced in the adrenal glands. Aldosterone has a central role in the homeostatic regulation of blood pressure and both plasma sodium (Na+) and potassium (K+) levels. Sodium restriction and a high potassium diet increases aldosterone production.
ACE and ACE2 Receptors
To summarize the information presented thus far, the RAAS system exists to modulate blood pressure, electrolyte balance, inflammation, apoptosis, and fibrosis throughout the body but more specifically for the heart, kidneys, testis, thyroid, small intestine, and colon. Angiotensin peptides bind to different ACE receptors, most notably ACE and ACE2, to exert effects that keep the biologic systems outlined above functioning optimally for survival.
Angiotension Converting Enzyme (ACE) and ACE 2 are glycoproteins that can exist in two forms, soluble and membrane-bound. Most ACE and ACE2 is membrane bound and is localized on the plasma membranes of various cell types. Though genetically similar, ACE and ACE2 receptors are antagonistic in their function, allowing angiotensin peptides multiple pathways for enzymatic cleavage in order to maintain a robust system of adaptability that can easily return to homeostasis.
ACE Receptor
Angiotension Converting Enzyme (ACE) is a glycoprotein which is most often expressed as a receptor site on a cell membrane but can also be a freely circulating solute in the bloodstream. ACE is primarily expressed by coronary endothelial cells and cardiac fibroblasts. ACE levels are also higher in the atria than the ventricles, and ACE is present in all four valves and the coronary vessels, aorta, pulmonary arteries, endocardium, and epicardium.
ACE hydrolyzes ANG I to ANG II, a potent vasoconstrictor. ACE also degrades a vasodilator bradykinin (BK) into BK1-7, an inactive metabolite. Bradykinin is a peptide that promotes inflammation, causing arterioles to dilate via the release of certain chemicals and makes veins constrict, increasing capillary pressure and leakage into capillary beds.
Through these mechanisms ACE receptors regulate vasoconstriction.
ACE2 Receptor
Angiotension Converting Enzyme 2 (ACE2) is an glycoprotein similar to ACE. There are two forms of ACE2, one is located on the cell membrane and the other is a soluble form that is shed into the circulatory system. ACE2 inhibits the formation of ANG II by ACE receptors by instead hydrolyzing ANG I to ANG1-9.
ACE2 can also hydrolyze existing ANG II to ANG1-7. ACE2 is 400-fold greater in its conversion of ANG II to ANG1-7 than it is in its ability to hydrolyze ANG I to ANG1-9. ANG1-7 generally opposes the actions of ANG II by stimulation of vasodilator prostaglandins from vascular endothelial and smooth muscles cells, release of nitric oxide, vasodilation, inhibition of vascular cell growth, and attenuation of ANG II induced vasoconstriction. The kidney is a major target organ for ANG1-7, is able to be produced there, and inhibits sodium absorption. ANG1-7 engenders an antidiuretic action that is due to reduction in glomerular filtration.
ANG1-7 is a major biologically active product of the RAAS, counterbalancing the actions of ANG II in the heart, blood vessels, and kidneys.
ACE2 does not convert ANG I to ANG II, instead ACE2 is an inhibitor of the formation of ANG II by stimulating alternate pathways for ANG I degradation while also degrading ANG II into ANG1-7.
ACE2 and SARS-CoV-2
ACE2 is the receptor site for the spike proteins of SARS-CoV-2. The spike proteins on the envelop of SARS-CoV-2 are cleaved into S1 and S2 subunits, with the S1 protein and ACE2 receptor interaction being the pivotal determinant for SARS-CoV-2 to infect a host species.
It is because of the ACE2 receptor is highly expressed in the tissues of small intestine, colon, and kidneys that explain why SARS-CoV-2 can cause gastrointestinal problems and kidney dysfunction. The ACE2 receptor is also highly expressed in the testis which supports the evidence that SARS-CoV-2 can cause reproductive problems. The ACE2 receptor is highly expressed in the tissues of the thyroid gland which explains the fatigue and malaise that SARS-CoV-2 can cause during infection, and the lasting effects labeled as “long covid”. Lastly, the ACE2 receptor is highly expressed in cardiac muscle which explains how SARS-CoV-2 can cause inflammation of the heart muscle, otherwise known as myocarditis.
SARS-CoV-2 and its fractions (spike protein) bind to the ACE2 receptor, reducing ACE2 receptor availability to convert angiotensin peptides as needed to maintain normal blood pressure and electrolyte balances. This alteration of function to the RAAS causes the the following effects:
Less conversion of ANG I to ANG1-9
Less conversion of ANG II to ANG1-7
SARS-CoV-2 does not bind to the ACE receptor, so the ability of ACE to convert ANG I to ANG II isn’t diminished. With ACE2 activity diminished though viral binding, more ANG II is produced by ACE and less ANG II is reduced to ANG1-7. The interaction between SARS-CoV-2 and ACE2 causes an accumulation of ANG II that causes vasoconstriction, the release of proinflammatory cytokines, oxidative stress, inflammation, atrophy, and fibrosis. Furthermore there is evidence that proinflammatory cytokines can cause the shedding of ACE2 receptors from cell membranes into solution, further increasing ANG II concentrations and worsening inflammation.
ANG II promotes endothelial dysfunction through the generation of vasoactive prostaglandins and reactive oxygen species, resulting in hypertension and atherosclerosis, and can induce apoptosis (programmed cell death). If the immune system is unable to halt SARS-CoV-2 reproduction and clear the system of the virus sufficiently, all these factors culminate into a hyperinflammatory state that can cause major tissue damage and if left unchecked, lead to death.
Also worth noting is the production of AGT (the precursor to ANG I and therefore ANG II) by adipose tissue. More adipose tissue produces a greater amount of AGT which in the context of reduced ACE2 receptor availability, will eventually result in greater levels of ANG II, further increasing blood pressure and inflammation.
The more health issues are present, namely obesity, high blood pressure, and cardiovascular disease, the greater the potential for SARS-CoV-2 to cause a chain-reaction of effects that results in massive inflammation throughout the body.
SARS-CoV-2 is a multisystemic disease which broadly effects the RAAS system while also acutely effecting the RAAS system in tissues with high expression of ACE2 receptors (heart, kidney, testis, thyroid, small intestine, colon). SARS-CoV-2 mRNA vaccines program cells to produce SARS-CoV-2 spike proteins in their cytoplasm, which are then transported and attached to the ACE2 receptors located on that cell’s membrane, causing a dysregulation of the RAAS system via reduced functionality of ACE2 receptors.
References:
Donoghue M, Hsieh F, Baronas E, et al. A novel angiotensin-converting enzyme–related carboxypeptidase (Ace2) converts angiotensin i to angiotensin 1-9. Circulation Research. 2000;87(5). https://doi.org/10.1161/01.res.87.5.e1
Carey RM, Siragy HM. Newly recognized components of the renin-angiotensin system: potential roles in cardiovascular and renal regulation. Endocrine Reviews. 2003;24(3):261-271. https://doi.org/10.1210/er.2003-0001
Scialo F, Daniele A, Amato F, et al. Ace2: the major cell entry receptor for sars-cov-2. Lung. 2020;198(6):867-877. https://dx.doi.org/10.1007%2Fs00408-020-00408-4