md_a
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- Aug 31, 2015
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Focus on the induction of antibodies by vaccines to define immunity has led to a dangerous disregard for the basic facts of health. The present testing of a vaccine containing the RNA that specifies the most destructive spike protein of the corona virus, the part that inactivates our protective ACE2 enzyme, is being done in a culture that avoids consideration of the meaning of our massive endogenous system of RNA-responsive reverse transcriptases and retroelements. The consequences of incorporating the spike protein of the virus into our genetic repertoire are hard to imagine. The mindless activation of our huge epigenetic system of retroelements, with no knowable benefits, should be stopped. – Ray Peat
The spike protein causes inflammation by inactivating the enzyme (ACE2) that inactivates angiotensin, so the spike protein essentially turns on our inflammatory system, the angiotensin system, and the RNA allows our own cells to manufacture spike protein, so we are being prepared to manufacture the activator of our own inflammatory system which is basically the only thing that causes people to die from Covid, if they die from it, mostly none of that diagnosis or determination of the cause of death, none of that has been done in a traditional scientific manner but to the extent that virus is harmful to week people, then is causing our body to produce the agent that kills people, and they ignore the fact that we have reverse transcriptase that can turn RNA to DNA and integrated it into our genes so that we can pass on the ability to destroy our defenses against inflammation. - Ray Peat
For years, corona viruses have been known to bind to the angiotensin converting enzyme 2 (ACE2), and that enzyme has been known to have protective effects, destroying angiotensin, and losartan, an angiotensin receptor blocker, has been known to be protective against corona viruses. Angiotensin increases intracellular calcium, and losartan lowers intracellular calcium. In reaction to the new corona virus, a few groups responded quickly, treating successfully with antiinflammatory things—losartan, cinanserin (a serotonin antagonist), aspirin, and azithromycin or erythromycin, which lower intracellular calcium. Aspirin’s effects overlap those of losartan, and it downregulates the angiotensin receptor, ATR1 (Mitra, et al., 2012). - Ray Peat
The problem is that our bodies can copy foreign RNA and DNA and incorporate the copies into our chromosomes. If they are genes for viral proteins, it’s possible that during a future stress, those foreign genes could be expressed throughout our body, creating overwhelming amounts of those toxic proteins. The copies could be inserted into sperm cells and eggs as well as body cells, forming part of future generations. No sane person would consider doing it, if they understood how our cells respond to alien nucleic acids.- Ray Peat
.....
Apparently, the acute accelerating lung fibrosis induced by COVID-19 infection can be justified through ACE – ACE2 - AT1 overactivation caused by the virus.
Studies indicate that ACE2 has a protective effect on the fibrogenesis and inflammation of different organs as well as liver and lung. Altogether given the several studies, the ACE-AngII-AT1 axis in the RAS system shows a predominant role in the organ fibrosis, particularly in lung and liver.
ACE2 has a regulatory effect on innate immunity and gut microbiota composition. Moreover, ACE2 has a determinant antifibrotic role in the lung injury induced by sepsis, acid aspiration, SARS, and lethal avian influenza A H5N1 virus.
The most common complication leading to the CoV-induced mortality is respiratory failure due to an extensive, accelerating lung fibrogenesis.
So, the acute accelerating lung fibrosis induced by COVID19 infection can be justified through ACE-AngII-AT1 overactivation caused by the virus.
Coronavirus is more severe and deadly in the aged, hypertensive, and diabetic.
It is also of note that ATR-1 Receptors increase with age and are increased in diabetes, hypertension, COPD. All of which are the populations at high risk for COVID-19. They are less in children, which is one reason hypertension is rare in children. As the SARS-COV2 virus attaches to the ACE2 it causes a decrease in ACE2 availability/activity. This would lead to a higher AngII and in patients with more AT-1, we would expect the effects would be worse, which is what we see in COVID-19. Another factor playing a role is that hypoxia causes cells to produce more AT-1. So, the localized edema in the lungs decreases oxygen, which increased AT-1, which further leads to edema.
Old people have a decreased expression of ACE2 (Angiotensin-converting enzyme 2), and increased expression of AT-1 receptors compared to the young.
If young people have higher ACE2, and that was the factor allowing faster viral inoculation, then it would be worse in the young, but it is not.
Cancer, hypertension, diabetes, allergies, autoimmune diseases, chronic obstructive pulmonary disease are all conditions that are associated with higher levels of the AT-1 receptor (Angiotensin II receptor type 1), with greater age or severity related to higher levels.
In patients with low ACE2 by age, sickness or virus binding to ACE2 means that it leaves the ACE1 which produces angiotensin.
ACE2 is capable in inactivating angiotensin breaking down to the first seven amino acids, they call it angiotensin 1-7, and this is a defensive anti-inflammatory peptide, so if your ACE2 is knocked out, angiotensin has a free range to cause damage, so the virus increases the inflammatory reaction by sticking to the defensive enzyme ACE2, and that enzyme combined with the virus, than acts to enter the cell by way of the Angiotensin II receptor type 1 which is called the AT1, that are two known receptors by which angiotensin can do damage, with stimulation of the larger population of AT-1 receptors within the local tissue eliciting further edema, leading to hypoxia witch upregulates the expression and function of AT1 receptor, with a whole range of destructive processes, nitric oxide production, pulmonary hypertension, acute lung injury and lung fibrosis.
Endotoxin (LPS) induced an increase in the AT1 subtype of the angiotensin II receptors.
Angiotensin-converting enzyme or ACE, is a central component of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. It converts the hormone angiotensin I to the active vasoconstrictor angiotensin II
ACE is also part of the kinin-kallikrein system where it degrades bradykinin, a potent vasodilator, and other vasoactive peptides.
Other less known functions of ACE are degradation of bradykinin and amyloid beta-protein.
Bradykinin is an inflammatory mediator. It is a peptide that causes blood vessels to dilate (enlarge) via the release of prostacyclin, nitric oxide, and Endothelium-Derived Hyperpolarizing Factor.
Bradykinin is a potent endothelium-dependent vasodilator and mild diuretic, which may cause a lowering of the blood pressure. It also causes contraction of non-vascular smooth muscle in the bronchus and gut, increases vascular permeability and is also involved in the mechanism of pain.
During inflammation, it is released locally from mast cells and basophils during tissue damage. Specifically, in relation to pain, bradykinin has been shown to sensitize TRPV1 receptors, thus lowering the temperature threshold at which they activate, thus presumably contributing to allodynia.
Bradykinin is also thought to be the cause of the dry cough, lack of smell and taste in some patients on widely prescribed angiotensin-converting enzyme (ACE) inhibitor drugs.
ACE inhibitors inhibit ACE competitively. That results in the decreased formation of angiotensin II and decreased metabolism of bradykinin, which leads to systematic dilation of the arteries and veins and a decrease in arterial blood pressure. In addition, inhibiting angiotensin II formation diminishes angiotensin II-mediated aldosterone secretion from the adrenal cortex, leading to a decrease in water and sodium reabsorption and a reduction in extracellular volume.
Therefore, ACE inhibitors, by blocking the breakdown of bradykinin, increase bradykinin levels, which can contribute to the vasodilator action of ACE inhibitors.
Angiotensin converting enzyme 2 (ACE2) - is a protein that sits on the lining cells within alveoli of the lung. It acts as an enzyme, being an exopeptidase that catalyses the conversion of Angiotensin II to angiotensin 1–7, which acts as a vasodilator. It also converts angiotensin I to nanopeptide angiotensin[1–9] It is a single-pass type I membrane protein expressed on the surface of epithelial cells of the pulmonary alveolus, and on small intestine enterocytes and other cell types.
ACE2 has been shown to be the entry point into human cells for some coronaviruses, including SARS-CoV, the virus that causes SARS. A number of studies have identified that the entry point is the same for SARS-CoV-2, the virus that causes COVID-19.
This might lead some to believe that decreasing the levels of ACE2, in cells, might help in fighting the infection. On the other hand, ACE2 has been shown to have a protective effect against virus-induced lung injury by increasing the production of the vasodilator angiotensin 1–7.
In fact, the interaction of the spike protein of the virus with the ACE2 induces a drop in the levels of ACE2 in cells.
Based on our examination of basic and clinical studies, we hypothesize that dysregulated bradykinin signaling is involved in COVID‐19 respiratory complications for the following reasons:
The severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), which causes COVID‐19, is known to enter host cells in the respiratory system via the transmembrane protein, angiotensin converting enzyme 2 (ACE2)
SARS‐CoV infection depletes ACE2
ACE2 depletion increases levels of des‐Arg(9)‐bradykinin (DABK), which is a bioactive metabolite of bradykinin that is associated with lung injury and inflammation.
A possible role for bradykinin in COVID‐19 respiratory distress is consistent with established evidence that, bradykinin, histamine, and serotonin, have for long been known as key mediators of acute lung inflammation and respiratory distress.
A loss of smell and/or taste has been reported by some patients with COVID‐19 and, a loss of smell has been reported in patients with angioedema and in persons who take ACE inhibitors.
Angiotensin excess causes the negative symptoms we associate with the virus - dry cough, fever, high blood pressure, etc.
.....
COVID-19 and Comorbidities
The Italian ISS (Caratteristiche dei pazienti deceduti positivi all'infezione da SARS-CoV-2 in Italia, accessed on April 26th 2020) reports that among 23,188 SARS-CoV-2 patients dying in Italy, 3.6% patients presented with no comorbidities, 14.4% with a single comorbidity, 21.1% with two, and 60.9% with three or more comorbidities. Among these comorbidities, the most represented is hypertension (69.1%), followed by ischemic heart disease (27.5%), chronic renal failure (21.1%), atrial fibrillation (22%), pulmonary diseases (17.1%), heart failure (16.1%), and some other comorbidities with <15% incidence. Of note is that all these pathologies are characterized by themselves by a downregulation of ACE2 and a high ACE/ACE2 ratio (10–14). The majority of deceased patients were aged (over 60) and obese (in the Italian report, obesity is present in 12.2% of deceased patients). In addition, these two conditions are characterized by an increasing ACE/ACE2 ratio (15, 16). Therefore, we wonder whether the invasion by SARS-CoV-2 and the downregulation of ACE2 are jointly responsible for a high incidence of dramatic acute respiratory distress syndrome (ARDS), cardiovascular complications, and high lethality of Covid-19. Is it worthwhile to try to re-establish an appropriate ACE/ACE2 ratio?
A natural way to upregulate membrane bound ACE2 and to lower the ACE/ACE2 ratio is to exercise. It has been reported several times that physical training, and especially aerobic training may decrease ACE/Ang II, and synergistic upregulates ACE2/Ang (1-7) axis (48, 49). Although someone has put forward the hypothesis that excessive exercise is a way to increase Trojan horses (ACE2) for SARS-CoV-2 invasion, the evidence for the beneficial effects attributable to regular exercise are overwhelming.
Are these subjects with a higher ACE2 and lower ACE/ACE2 ratio also protected against Covid-19 exacerbation? ACE2 expression could influence the course of Covid-19 in different ways: increased expression might promote viral entry, whereas ACE2 increased expression may be beneficial due to ACE2 anti-inflammatory and other beneficial effects (Figure 1) that could prevent pulmonary edema, ARDS, hypoxia, and redox stress development. It is likely that viral load is not strictly related to disease severity, and so it is likely that ACE2 overexpression is not responsible for Covid-19 worsening but that there is, rather, some other mechanism within the complex RAS or outside of RAS (such as a different macrophages population or a different immune response) that may play a role. Covid-19 is associated with an exaggerated and dysregulated systemic inflammatory response involving several inflammatory cells and leading to overproduction of several cytokines. We recently discussed in a Review article (25) the cells and the cytokines likely involved in the exacerbation of Covid-19. We pointed out how cytokine storms on cardiac and vascular endothelium may facilitate the onset of coagulopathies, thereby increasing the probability for organ ischemia and for multiple pulmonary and cardiovascular complications. The virus downregulates ACE2, exacerbating the pro-inflammatory milieu of high ACE/ACE2 ratio.
Membrane-bound ACE2 has an anti-inflammatory role, and an imbalanced and high ACE/ACE2 ratio is not recommended (Figure 1): it is better to have a low ACE/ACE2 ratio. Whether increasing the ACE2/Ang (1-7) axis by pharmacological intervention or by regular exercise may limit Covid-19 worsening remains to be ascertained. Of course, these hypotheses deserve to be studied and must be confirmed with ad hoc researches. Nevertheless, currently there are no effective and definitively approved drugs for the treatment of Covid-19. Therefore, understanding the molecular and cellular mechanisms that favors or exacerbates the Covid-19 in patients with altered ACE/ACE2 ratio and with comorbidities in general is urgent and necessary to design some truly effective therapies. In the meantime, we await a therapy or a vaccine; we can exercise, though we recommend to do this at home or alone to limit the diffusion of this terrible pandemic.
A hypothesized role for dysregulated bradykinin signaling in COVID‐19 respiratory complications
ACE/ACE2 Ratio: A Key Also in 2019 Coronavirus Disease (Covid-19)?
cardiovascularnews.com
The spike protein causes inflammation by inactivating the enzyme (ACE2) that inactivates angiotensin, so the spike protein essentially turns on our inflammatory system, the angiotensin system, and the RNA allows our own cells to manufacture spike protein, so we are being prepared to manufacture the activator of our own inflammatory system which is basically the only thing that causes people to die from Covid, if they die from it, mostly none of that diagnosis or determination of the cause of death, none of that has been done in a traditional scientific manner but to the extent that virus is harmful to week people, then is causing our body to produce the agent that kills people, and they ignore the fact that we have reverse transcriptase that can turn RNA to DNA and integrated it into our genes so that we can pass on the ability to destroy our defenses against inflammation. - Ray Peat
For years, corona viruses have been known to bind to the angiotensin converting enzyme 2 (ACE2), and that enzyme has been known to have protective effects, destroying angiotensin, and losartan, an angiotensin receptor blocker, has been known to be protective against corona viruses. Angiotensin increases intracellular calcium, and losartan lowers intracellular calcium. In reaction to the new corona virus, a few groups responded quickly, treating successfully with antiinflammatory things—losartan, cinanserin (a serotonin antagonist), aspirin, and azithromycin or erythromycin, which lower intracellular calcium. Aspirin’s effects overlap those of losartan, and it downregulates the angiotensin receptor, ATR1 (Mitra, et al., 2012). - Ray Peat
The problem is that our bodies can copy foreign RNA and DNA and incorporate the copies into our chromosomes. If they are genes for viral proteins, it’s possible that during a future stress, those foreign genes could be expressed throughout our body, creating overwhelming amounts of those toxic proteins. The copies could be inserted into sperm cells and eggs as well as body cells, forming part of future generations. No sane person would consider doing it, if they understood how our cells respond to alien nucleic acids.- Ray Peat
.....
Apparently, the acute accelerating lung fibrosis induced by COVID-19 infection can be justified through ACE – ACE2 - AT1 overactivation caused by the virus.
Studies indicate that ACE2 has a protective effect on the fibrogenesis and inflammation of different organs as well as liver and lung. Altogether given the several studies, the ACE-AngII-AT1 axis in the RAS system shows a predominant role in the organ fibrosis, particularly in lung and liver.
ACE2 has a regulatory effect on innate immunity and gut microbiota composition. Moreover, ACE2 has a determinant antifibrotic role in the lung injury induced by sepsis, acid aspiration, SARS, and lethal avian influenza A H5N1 virus.
The most common complication leading to the CoV-induced mortality is respiratory failure due to an extensive, accelerating lung fibrogenesis.
So, the acute accelerating lung fibrosis induced by COVID19 infection can be justified through ACE-AngII-AT1 overactivation caused by the virus.
Coronavirus is more severe and deadly in the aged, hypertensive, and diabetic.
It is also of note that ATR-1 Receptors increase with age and are increased in diabetes, hypertension, COPD. All of which are the populations at high risk for COVID-19. They are less in children, which is one reason hypertension is rare in children. As the SARS-COV2 virus attaches to the ACE2 it causes a decrease in ACE2 availability/activity. This would lead to a higher AngII and in patients with more AT-1, we would expect the effects would be worse, which is what we see in COVID-19. Another factor playing a role is that hypoxia causes cells to produce more AT-1. So, the localized edema in the lungs decreases oxygen, which increased AT-1, which further leads to edema.
Old people have a decreased expression of ACE2 (Angiotensin-converting enzyme 2), and increased expression of AT-1 receptors compared to the young.
If young people have higher ACE2, and that was the factor allowing faster viral inoculation, then it would be worse in the young, but it is not.
Cancer, hypertension, diabetes, allergies, autoimmune diseases, chronic obstructive pulmonary disease are all conditions that are associated with higher levels of the AT-1 receptor (Angiotensin II receptor type 1), with greater age or severity related to higher levels.
In patients with low ACE2 by age, sickness or virus binding to ACE2 means that it leaves the ACE1 which produces angiotensin.
ACE2 is capable in inactivating angiotensin breaking down to the first seven amino acids, they call it angiotensin 1-7, and this is a defensive anti-inflammatory peptide, so if your ACE2 is knocked out, angiotensin has a free range to cause damage, so the virus increases the inflammatory reaction by sticking to the defensive enzyme ACE2, and that enzyme combined with the virus, than acts to enter the cell by way of the Angiotensin II receptor type 1 which is called the AT1, that are two known receptors by which angiotensin can do damage, with stimulation of the larger population of AT-1 receptors within the local tissue eliciting further edema, leading to hypoxia witch upregulates the expression and function of AT1 receptor, with a whole range of destructive processes, nitric oxide production, pulmonary hypertension, acute lung injury and lung fibrosis.
Endotoxin (LPS) induced an increase in the AT1 subtype of the angiotensin II receptors.
Angiotensin-converting enzyme or ACE, is a central component of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. It converts the hormone angiotensin I to the active vasoconstrictor angiotensin II
ACE is also part of the kinin-kallikrein system where it degrades bradykinin, a potent vasodilator, and other vasoactive peptides.
Other less known functions of ACE are degradation of bradykinin and amyloid beta-protein.
Bradykinin is an inflammatory mediator. It is a peptide that causes blood vessels to dilate (enlarge) via the release of prostacyclin, nitric oxide, and Endothelium-Derived Hyperpolarizing Factor.
Bradykinin is a potent endothelium-dependent vasodilator and mild diuretic, which may cause a lowering of the blood pressure. It also causes contraction of non-vascular smooth muscle in the bronchus and gut, increases vascular permeability and is also involved in the mechanism of pain.
During inflammation, it is released locally from mast cells and basophils during tissue damage. Specifically, in relation to pain, bradykinin has been shown to sensitize TRPV1 receptors, thus lowering the temperature threshold at which they activate, thus presumably contributing to allodynia.
Bradykinin is also thought to be the cause of the dry cough, lack of smell and taste in some patients on widely prescribed angiotensin-converting enzyme (ACE) inhibitor drugs.
ACE inhibitors inhibit ACE competitively. That results in the decreased formation of angiotensin II and decreased metabolism of bradykinin, which leads to systematic dilation of the arteries and veins and a decrease in arterial blood pressure. In addition, inhibiting angiotensin II formation diminishes angiotensin II-mediated aldosterone secretion from the adrenal cortex, leading to a decrease in water and sodium reabsorption and a reduction in extracellular volume.
Therefore, ACE inhibitors, by blocking the breakdown of bradykinin, increase bradykinin levels, which can contribute to the vasodilator action of ACE inhibitors.
Angiotensin converting enzyme 2 (ACE2) - is a protein that sits on the lining cells within alveoli of the lung. It acts as an enzyme, being an exopeptidase that catalyses the conversion of Angiotensin II to angiotensin 1–7, which acts as a vasodilator. It also converts angiotensin I to nanopeptide angiotensin[1–9] It is a single-pass type I membrane protein expressed on the surface of epithelial cells of the pulmonary alveolus, and on small intestine enterocytes and other cell types.
ACE2 has been shown to be the entry point into human cells for some coronaviruses, including SARS-CoV, the virus that causes SARS. A number of studies have identified that the entry point is the same for SARS-CoV-2, the virus that causes COVID-19.
This might lead some to believe that decreasing the levels of ACE2, in cells, might help in fighting the infection. On the other hand, ACE2 has been shown to have a protective effect against virus-induced lung injury by increasing the production of the vasodilator angiotensin 1–7.
In fact, the interaction of the spike protein of the virus with the ACE2 induces a drop in the levels of ACE2 in cells.
Based on our examination of basic and clinical studies, we hypothesize that dysregulated bradykinin signaling is involved in COVID‐19 respiratory complications for the following reasons:
The severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), which causes COVID‐19, is known to enter host cells in the respiratory system via the transmembrane protein, angiotensin converting enzyme 2 (ACE2)
SARS‐CoV infection depletes ACE2
ACE2 depletion increases levels of des‐Arg(9)‐bradykinin (DABK), which is a bioactive metabolite of bradykinin that is associated with lung injury and inflammation.
A possible role for bradykinin in COVID‐19 respiratory distress is consistent with established evidence that, bradykinin, histamine, and serotonin, have for long been known as key mediators of acute lung inflammation and respiratory distress.
A loss of smell and/or taste has been reported by some patients with COVID‐19 and, a loss of smell has been reported in patients with angioedema and in persons who take ACE inhibitors.
Angiotensin excess causes the negative symptoms we associate with the virus - dry cough, fever, high blood pressure, etc.
.....
COVID-19 and Comorbidities
The Italian ISS (Caratteristiche dei pazienti deceduti positivi all'infezione da SARS-CoV-2 in Italia, accessed on April 26th 2020) reports that among 23,188 SARS-CoV-2 patients dying in Italy, 3.6% patients presented with no comorbidities, 14.4% with a single comorbidity, 21.1% with two, and 60.9% with three or more comorbidities. Among these comorbidities, the most represented is hypertension (69.1%), followed by ischemic heart disease (27.5%), chronic renal failure (21.1%), atrial fibrillation (22%), pulmonary diseases (17.1%), heart failure (16.1%), and some other comorbidities with <15% incidence. Of note is that all these pathologies are characterized by themselves by a downregulation of ACE2 and a high ACE/ACE2 ratio (10–14). The majority of deceased patients were aged (over 60) and obese (in the Italian report, obesity is present in 12.2% of deceased patients). In addition, these two conditions are characterized by an increasing ACE/ACE2 ratio (15, 16). Therefore, we wonder whether the invasion by SARS-CoV-2 and the downregulation of ACE2 are jointly responsible for a high incidence of dramatic acute respiratory distress syndrome (ARDS), cardiovascular complications, and high lethality of Covid-19. Is it worthwhile to try to re-establish an appropriate ACE/ACE2 ratio?
Approaches to Improve Ace/Ace2 Ratio
All the above data support the idea that an imbalance in the ACE/ACE2 ratio may be a predisposing cause to the worsening of the Covid-19. It has also been suggested that the increased concentration of ACE2 receptors in in the lungs of children may have a protective effect on severe clinical manifestations due to SARS-CoV-2 invasion (36). Also, these data support a negative correlation between ACE2 expression and Covid-19 severe outcomes. Perhaps, therapies improving this ratio may be useful in infected patients (37–40). The RAS is quite complex, and several pharmacological approaches are under evaluation to benefit from ACE downregulation and ACE2 upregulation in a variety of pathological conditions, especially cardiovascular diseases. ACE inhibitors (ACEi) and AT1R blockers (ARB) upregulate the expression of ACE2 (37–40). Potential direct activators of ACE2 are diminazene aceturate, resorcinolnaphthalein, and xanthenone (41). Since SARS-CoV-2 spreads via the bloodstream to infect other organs, recombinant ACE2 (rhACE2) has been proposed as a therapeutic approach in pneumonia and Covid-19 (42–44). The soluble rhACE2 may be a promising approach to quench the virus when it is in the bloodstream (43, 44). However, it must be tested with caution, as soluble ACE2 is not always associated with beneficial effects (45). For instance, soluble ACE2 has a high level in men suffering from heart failure (45, 46). However, as said above, this is a condition associated with Covid-19 worsening; and this therefore suggests that soluble ACE2 may not be sufficient to protect patients. Membrane-bound ACE2 has greater anti-inflammatory effects (47).A natural way to upregulate membrane bound ACE2 and to lower the ACE/ACE2 ratio is to exercise. It has been reported several times that physical training, and especially aerobic training may decrease ACE/Ang II, and synergistic upregulates ACE2/Ang (1-7) axis (48, 49). Although someone has put forward the hypothesis that excessive exercise is a way to increase Trojan horses (ACE2) for SARS-CoV-2 invasion, the evidence for the beneficial effects attributable to regular exercise are overwhelming.
Discussion and Conclusions
All in all, the majority of data are in favor of the idea that a high ACE/ACE2 ratio may be detrimental for Covid-19 infection. ACE/ACE2 ratio is increased in many pathologies (especially dis-metabolisms and cardiovascular diseases) and conditions (obesity and aging) that exacerbate Covid-19 symptomatology and worsen outcomes. Moreover, ACE2 is upregulated and the ACE/ACE2 ratio is lower in many subjects at low risk for cardiovascular diseases, such as females, exercise-trained individuals, and patients well-treated with ACE inhibitors. Since most of the deceased Covid-19 patients had hypertension, further consideration is needed for ACEi and ARBs. The use of these drugs has been questioned, but the majority of authors are in favor of the use of these drugs (37–42). We agree that if used correctly they reduce the ACE / ACE2 ratio and should also be recommended to Covid-19 patients.Are these subjects with a higher ACE2 and lower ACE/ACE2 ratio also protected against Covid-19 exacerbation? ACE2 expression could influence the course of Covid-19 in different ways: increased expression might promote viral entry, whereas ACE2 increased expression may be beneficial due to ACE2 anti-inflammatory and other beneficial effects (Figure 1) that could prevent pulmonary edema, ARDS, hypoxia, and redox stress development. It is likely that viral load is not strictly related to disease severity, and so it is likely that ACE2 overexpression is not responsible for Covid-19 worsening but that there is, rather, some other mechanism within the complex RAS or outside of RAS (such as a different macrophages population or a different immune response) that may play a role. Covid-19 is associated with an exaggerated and dysregulated systemic inflammatory response involving several inflammatory cells and leading to overproduction of several cytokines. We recently discussed in a Review article (25) the cells and the cytokines likely involved in the exacerbation of Covid-19. We pointed out how cytokine storms on cardiac and vascular endothelium may facilitate the onset of coagulopathies, thereby increasing the probability for organ ischemia and for multiple pulmonary and cardiovascular complications. The virus downregulates ACE2, exacerbating the pro-inflammatory milieu of high ACE/ACE2 ratio.
Membrane-bound ACE2 has an anti-inflammatory role, and an imbalanced and high ACE/ACE2 ratio is not recommended (Figure 1): it is better to have a low ACE/ACE2 ratio. Whether increasing the ACE2/Ang (1-7) axis by pharmacological intervention or by regular exercise may limit Covid-19 worsening remains to be ascertained. Of course, these hypotheses deserve to be studied and must be confirmed with ad hoc researches. Nevertheless, currently there are no effective and definitively approved drugs for the treatment of Covid-19. Therefore, understanding the molecular and cellular mechanisms that favors or exacerbates the Covid-19 in patients with altered ACE/ACE2 ratio and with comorbidities in general is urgent and necessary to design some truly effective therapies. In the meantime, we await a therapy or a vaccine; we can exercise, though we recommend to do this at home or alone to limit the diffusion of this terrible pandemic.
A hypothesized role for dysregulated bradykinin signaling in COVID‐19 respiratory complications
ACE/ACE2 Ratio: A Key Also in 2019 Coronavirus Disease (Covid-19)?
Decreased ACE2 levels found in ageing and cardiovascular disease can increase likelihood of severe COVID-19 - Cardiovascular News
The reduced levels of angiotensin converting enzyme (ACE) 2 associated with cardiovascular disease and increasing age lead to a higher susceptibility to greater disease severity in COVID-19. A viewpoint published online in JAMA Cardiology hypothesises that severe acute respiratory syndrome...
cardiovascularnews.com
