Coronavirus Pandemic Update 63: Is COVID-19 a Disease of the Endothelium (Blood Vessels and Clots)?

welcome to another

update

from make cram cove on nineteen daily new cases in the United States are decreasing, however, daily deaths are not, but are generally lagging. I wanted to take a look at a couple of other countries here, this is Brazil, daily new cases going. to an all-time high as our daily deaths also in India total cases are starting to rise persistently as are daily deaths in India cases in Iran peaked about a month ago and have come down and stabilized at about a thousand daily cases of deaths have had a similar behavior. We have been looking at Finland when talking about saunas and hydrothermal therapy.

Those cases are also starting to decline. On the other hand, Sweden's cases appear to be wavering but are not actually declining. In a particular direction, in the last number of videos we have been talking about the endothelial system as a potential target for the corona virus and I want to show you what it looked like. This is the lumen of an artery and you can see here the The white area is where red

blood

cells and

blood

move and that endothelial lining covers every aspect of the wall of this artery. These are very thin cells and they control all kinds of things and when they become inflamed certain things can happen, we'll talk about it.

I have now done a lot of research on those things looking for articles and I think a picture is emerging of what happens when the SARS bracelet infects a human being. I don't have all the dots connected, but there is a picture. that is emerging and many people have been affected and many people have died as a result of this and I think you and society deserve a possible explanation for why we are seeing the things we are seeing, why the ventilators are not doing what I thought. What were they going to do? Why are there certain patients who behave as if they were at a high altitude?

Why do they have very flexible lungs when we would expect them to have very non-flexible lungs? Why do some young patients suffer strokes? Blood

clots

. Because? Are some patients improving and even being extubated or taken off the ventilator only to go into cardiac arrest or be discharged home and then return very sick? I think one possible answer lies in the explanation that Kovat 19 is an endothelial

disease

and uses the lungs to enter the body and certainly causes

disease

in the lungs, but once they enter the body that is where they cause the most damage. Now, in the next series of videos, what I would like to do is explain exactly what I want.

I'm talking about using articles and research from peer-reviewed journals, but in order for you to understand a lot of what we're talking about, we're going to use the language of oxidative stress and in order for you to fully understand we're going to have to go. Go back to medical school and refresh some basics, so bear with us while we go over some basic ideas in terms of metabolism, oxidation, energy production, and some plain old biochemistry. The first thing we have to talk about is the batteries in your cell. They are called mitochondria and exist in the cell to produce energy.

They also have their own DNA called mitochondrial DNA, which we will talk about later. Notice that in mitochondria there's something called the matrix, which is this thing in the center, it's a space in the center and then there's a space around the edge called the intermembrane space and that's because it's between two membranes that will become important. later. Here we have drawn it schematically. Here's the matrix in the middle and the intermembrane space around the outside. When you eat food there are only three types of products that really matter and they are carbohydrates, fats and proteins, regardless of which one it is, for now we will simplify a little with this, all of these things can eventually be divided into two units of carbon.

In this case it is called active Eelco a and then what happens is that it enters a cycle called the Krebs cycle. Well, we'll just call it Circle K. What happens here is when you go through that cycle a lot of metabolism occurs and that's what you basically get out of. electrons the important thing is that these electrons are tied up in something called n a d h and fadh2 these electrons are what we call reduced which means they would love to be abandoned you will hear me use that term reduced does not mean lower and amplitude means the opposite of oxidized which What we mean by that is that if you have something like a and B and a has an electron and it gives that electron to B, then what we're saying is that B was reduced and a was oxidized.

In other words, when something loses an electron, it is oxidized and when something gains an electron, we say it is reduced. Because these nadh and fadh2 are electron rich, they love to go out and reduce things, in other words they oxidize but reduce some more in the process, so keep that in mind and let's back up a little and talk about why we're here first of all. Carbohydrates, fats and proteins are fuel for our body and when fuel is put into a car engine. What you are trying to get is the angular momentum or the rotational moment of the wheel so that it can rotate and you can get energy and that energy is put to good use either by turning an alternator and getting electricity or by turning a wheel and moving from one place to another. to another here we obviously want something a little different.

The end goal is to get something called TP which stands for adenosine triphosphate, which is basically an adenosine with three phosphate molecules and what the body does with energy. you just remove one of those phosphates and what you get is energy and to get that energy back you just take a bunch of energy to put that phosphate back in well what are you putting it back in? You're putting him back on an adenosine DP. diphosphate, so when you go from adenosine diphosphate to identity triphosphate, you have to add energy; When you go from ATP to ADP, you get energy, so this is the fuel for the body and that is the currency of energy in the body, generally speaking, everything is used up. of ATP, so how are we going to go from carbohydrates, fats and proteins to ATP?

This is what mitochondria are for, so carbohydrates, fats and proteins are broken down into two carbon units, they go through this Krebs cycle, the Krebs cycle takes these things and basically metabolizes them into electrons that can circulate and be reduced. So what happens now? These electrons go here to this membrane where there are proteins in the membrane, so the Krebs cycle electrons that are represented by NADH are ready to go to the intermembrane space to give electrons are ready to give up and there are proteins that are willing to give up. accept it and when that happens, let's expand this a little bit to describe exactly what we're looking at, so here we have the membrane, we have the space between membranes. and we have these electrons and we have proteins in the membrane, so when these electrons come in, they get to the top of the reduced electron scale, so to speak, and what they do is when they give up their electron, they give it to a lower group and they lose some of that reduction and in the process of doing that, as they go from a reduced state to a lower reduced state, the protons are pumped into the intermembrane space and then they go to another species that is a little bit smaller . a little more oxidized and that pumps more protons into the intermembrane space, it keeps pumping and pumping until the protons build up in this inner membrane space and therefore you have such a high concentration of protons in the inner membrane space that the pH in this inner membrane space is actually quite low and we'll talk about what happens after that, but ultimately what happens is that this electron that started here got reduced and wanting to reduce other things it oxidizes and finally gets to this point where it is no longer so reduced. as it once was, the only thing it can now reduce is the most oxidized molecule, perhaps in the human body, in that case it is oxygen itself, oxygen will take this electron and eventually become here, take that electron into water, so you can see. why oxygen is so important for the human body because without oxygen here it could not accept the electron at the end and if it could not accept the electron at the end it would be like a traffic accident, everything would go backwards and there would be no movement of electrons and if not If there were electron movement, the protons would not move into the intermembrane space, so why is it important to have protons in the intermembrane space because the protons in your intermembrane space want to return to the matrix where?

There is a low concentration of protons, so they pass through a channel and that channel is coupled so that when they pass, like a dam on the Colorado River, it spins a turbine. As these protons pass through here, there is ADP coupling, as you might have guessed. in a teepee and finally now we have our currency, so how do we go from carbohydrates back to fats and proteins to ATP? It is metabolized into two carbon units. The two carbon units enter the Krebs cycle. The Krebs cycle converts it into electrons. they go to the inner membrane space where, as they move down the electron transport chain to increasingly oxidized carriers, they eventually reach the most oxidized electron acceptor, which is oxygen, which then converts it to water and reduces the oxygen to water, but in the process of this.

In the electron transport chain we get protons that are placed in the internal membrane space, this accumulates with a lot of concentration and then descends from the internal membrane space to the matrix coupling adp into ATP and now the body has energy if, on the other hand, your cells don't get enough oxygen, so the electron transport chain goes backwards, the protons can no longer move into the inner membrane space, therefore there is no cascade going down, therefore no It has ATP and the cell loses energy and dies. There are a couple of points I want to make here, number one: if you were to follow a diet with a rapid metabolism of carbohydrates, fats and proteins, you would find yourself with a surplus of electrons ready to move into the electron transport chain, even though this is a regulated series of metabolism, as you can see there, a high carbohydrate, high fat diet will quickly give you a lot of electrons in the matrix of the mitochondria, so there is good data that excessive calorie consumption coming from a high diet high carbohydrate or high fat will cause more of these two carbon units to go into the mitochondrial Krebs cycle and then what will come out is more electrons, of course, which go to the electron transport chain, which is number one, the Number two, is that oxygen is ready to accept whatever type of electrons it is ready to accept. electrons down here in the electron transport chain and if you are ready to accept electrons here in the electron transport chain you could certainly accept electrons anywhere along this path because more than any other species in the body it loves electrons.

Fortunately these electrons are kept in the form of nadh and fadh2, which is pretty tightly regulated, but sometimes if there's too much nadh or fadh2, that can go wrong, so the next thing we need to talk about is what happens if oxygen up here starts pulling electrons out of the electron transport chain, whether because unfortunately or on purpose, let's talk about superoxides, okay, this is what you really have to listen to and refer to this and slow down if it's too fast because this is really important. We're going to talk about oxygen here, so let's talk. about oxygen being available to be the final electron acceptor in the electron transport chain, so what we're going to do is go over this and show you what happens every time we add an electron when we add an electron to oxygen. get something called superoxide and I'm going to put a big dot here to symbolize the fact that it has a single electron added every time a single electron is added to it, in this case this becomes what we call a radical, so every time So we see this point, this is a radical, which means this can be very reactive and it's very dangerous and it can actually cause damage to your DNA and cause very serious inflammation, that's important because the body actually uses this to kill. bacteria and we'll talk about that.

Furthermore, if we added another electron we would obtain hydrogen peroxide. We know that hydrogen peroxide also kills. If we add another electron, we will get something called a hydroxy radical again. I'm going to make a big point here. So you can see that that is a dangerous species, if we add another electron, we finally get to the water, so the ones that are dangerous are the ones that have the hydroxy radical and the superoxide. I'm going to put the name of this here. You can see this is known as superoxide and it is a hydroxy radical, this is bad for living things, so if you have something inside you that you want to kill, the cells will produce neutrophils etc, that is exactly what they do. in neutrophils there is something called d ph oxidase anything that ends in an ace is an enzyme so NADPH oxidase is an enzyme that oxidizes NADPH when it is oxidized it is actually reducing oxygen to the radicalsuperoxide, so this is a bad player.

You're a bad player, so when these things start to build up in your cells, your body has to have a defense mechanism to get rid of these things. Hydrogen peroxide is not a radical, but it is not exactly the best either, so we have to find solutions. So one of the enzymes that is really one of the big solutions for superoxide to build up in the body is something called superoxide dismutase and that's an important thing to understand, so superoxide dismutase takes the superoxide molecule, actually It takes two of them and converts them into oxygen. molecule and in a molecule of hydrogen peroxide, in other words, it gives one of these electrons to the other species and converts one of them to oxygen and the other to hydrogen peroxide, so there are three types of superoxide dismutase: the type 1, type 2 and type 3, one of these is in the mitochondria, another is in the cytosol and another. one is in the extracellular matrix and just so you know, the elements that are required for this enzyme to function in a very interesting way are zinc, copper and when we talk about the mitochondrial version of this mineral manganese MN, these are very essential. elements so that the superoxide dismutase can work on the superoxide to get rid of it which still leaves us with this hydrogen peroxide, so the next enzyme that is very essential is something called glutathione peroxidase which will be abbreviated as G SH px glutathione peroxidase does exactly what do you think would work?

It takes peroxide and reduces it by giving two electrons to the water. Where does glutathione get those two electrons? It can be in two forms, an oxidized form and a reduced form, and when it's in the reduced form, you have two. glutathione equivalents with an S and a hydrogen bond to that sulfur group, however when it is oxidized it will look like this G s s G in other words the hydrogen goes away and you have what we call a disulfide bond, how does that work? Here you have the reduced form in this redox reaction the reduced form comes in here glutathione peroxidase donates those two electrons to hydrogen peroxide converting it and reducing it to harmless water so how do we recharge our glutathione system?

Well, we have to reduce it again the way we reduced it. back it is with NADPH that has the two electrons and that converts it into a DP plus and that is done through glutathione reductase, why do we call it that? Because we are reducing glutathione, so here the electrons come from NADPH and go into this form which is the reduced form of glutathione, then glutathione uses glutathione peroxidase to reduce the peroxide to harmless water. Now there is another system that you should know about and it is known as catalase. Catalase can take hydrogen peroxide and turn it into water, two molecules of hydrogen peroxide and convert the other to oxygen and that happens in the peroxisomes, those are small organelles in the cell and the element that is required for that to happen is iron, so what do I want you to know?

I want you to know that superoxide is very bad. molecule and it can cause a lot of damage, it can cause oxidative stress, so the body has to find ways to solve that problem. One of the most important ways is with superoxide dismutase, which requires zinc, copper and manganese. Another way to get rid of this. It's glutathione peroxidase, glutathione peroxidase then takes the resulting hydrogen peroxide and can turn it into water if these systems don't work, what happens is superoxide builds up and that means a buildup of oxidative stress and that can lead to disease now, a Sometimes, in the literature, superoxide is sometimes referred to in general as our operating system or reactive oxygen species which will refer to superoxide, hydrogen peroxide, and hydroxy radicals, so when you see these three, they are known as together as reactive oxygen species and these are things that cause disease, okay, let's test our new knowledge and see if it's going to give us any wisdom.

Here is an article that was published back in 2008, titled Angiotensin-converting enzyme, which is the target of the SARS PUP, confers endothelial protection and attenuates atherosclerosis, so let's delve into the article and see if we can now make sense of this , here's a section called ace: modulates angiotensin, ro s induced by those are the production species of reactive oxygen species in endothelial cells, so back in 2008 we knew that here it says an important source of reactive oxygen species in endothelial cells. is NADPH oxidase, remember that's what we said here NADPH oxidase causes these reactive species which in turn generates reactive oxygen species within the endothelial cells angiotensin ii remember that angiotensin ii was the byproduct of ACE and this is a diseased filling molecule that causes vasoconstriction this molecule is supposed to be metabolized by a stew to angiotensin 1 7, which is a vasodilator, let's find out what they say here.

Angiotensin 2 induced the generation of reactive oxygen species as assessed by this dye. Hi Joe Etha, diem's ​​fluorescence was quenched by stew, that's exactly what we would expect. Remember. stew is the protein that is inactivated when the virus binds to it and this effect was attenuated by inhibition of angiotensin 1 7. We extend these observations further by providing data that the effects of angiotensin 2 to upregulate the expression of P 22 fox are attenuated by ace 2, in other words ace 2, the protein that is the target of the virus is being downregulated and is no longer able to suppress angiotensin induction of reactive oxygen species.

He goes on to say that these effects are also inhibited by a 779 which is what they used in the experiments, they said here that angiotensin 2 induces an increase in MC p1 and v-cam 1 in endothelial cells and is also attenuated by ace 2 and these effects are also mitigated during the incubation of Co with a 7 7 9 and just so you know, 7 7 9 is a molecule that blocks the effect of angiotensin 1 7 the product of a Stu so here is a summary of this paragraph These data suggest that Ace 2 is the virus's target in an angiotensin 7-dependent manner and functions to improve endothelial homeostasis through a mechanism that may involve attenuation or reduction of NADPH oxidase-induced RoS production. so let's go back to our graph and see if we can modify it, so what they are saying here is that angiotensin one 7 slows down pH nad oxidase, but remember that angiotensin 1-7 is the product of angiotensin ii and it is converted by ACE, but the SARS cuff destroys ACE, so what we have here is an inhibition of inhibition, which means that NADPH oxidase is allowed to reach its maximum level. pierce through and produce these bad superoxide molecules, so the question is if someone has cardiovascular disease, diabetes or obesity where superoxide dismutase doesn't work and glutathione peroxidase doesn't work and you already have one or two oxidative impacts. stress balance and now, suddenly, the only thing that kept NADPH oxidase in check was angiotensin one 7 and now with the virus it eliminates the ACE that produces that angiotensin 1 7 and now you have the free reign of NADPH oxidase.

We are going to have a huge buildup of superoxide in the system and that superoxide is going to cause endothelial damage and that is perhaps what we are seeing in Cova 19 and now that you understand the language in the next lectures we are going to talk more about the studies that show that this may actually be what is happening. Thanks for joining us and I look forward to seeing you on Thursday for the live webinar.