What causes atherosclerosis?

I have already discussed here several times that the main actor in the formation of narrowed blood vessels and plaque is not cholesterol, as official medicine still tells us, but oxidative stress. I showed that oxalic acid (oxalate) and its neutralization by calcium in food play a big role here.

In this post, I will continue following the trail of the AMPK enzyme, which controls the phosphorylation of very important enzymes related to some civilization diseases. For example, it phosphorylates the enzyme ACC and thus suppresses the formation of new fats and thus solves obesity. AMPK suppresses hepatic glucose production and gluconeogenesis and thus resolves diabetes. And in this post we will see how activation (phosphorylation) of AMPK reduces oxidative stress on the inner surface of blood vessels (endothelium) and thus suppresses atherosclerosis. So I am continuing the serie that monitors the effects of acetate on the metabolism of liver and fat cells, brain cells and now also vascular endothelial cells.

Turbulent blood flow in the aortic arch (AA) versus laminar flow in a straight section of the aorta (TA). MitoSOX indicates the occurrence of oxidative stress (superoxide).

You must have thought it strange, like me, that the deposition of vascular plaque occurs only in the arteries, at the branches of the arteries, on the coronary arteries, i.e. the heart arteries, i.e. in the most mechanically stressed places. It's not a coincidence. An explanation can be found in this study that examines the effect of flow, the difference between laminar and turbulent flow.

Laminar blood flow induces stable endothelium stress in one direction (USS) and thus activates the KLF2 transcription factor in it and triggers the production of the UCP2 enzyme. On the contrary, turbulent flow (OSS) induces rapid changes in direction and variable stress on the endothelium, which suppresses KLF2 activity and prevents the production of the UCP2 enzyme.

What does the UCP2 enzyme do? This enzyme settles in the inner mitochondrial membrane and releases the accumulated electrical energy. We already know that the inner mitochondrial membrane behaves like the insulating layer of a capacitor. Electrons bound to hydrogen atoms in the molecules of our food move to hydrogen atoms bound to oxygen, thus forming water. The released energy charges the capacitor by pumping protons. The voltage created is no higher than 150 mV, but with the thickness of the insulating membrane only about 5 nm, the electric field strength is enormous, in the order of 30 million volts per meter, this drives the production of ATP in the Complex V.

If energy is not being taken, the highly charged mitochondrial capacitor refuses to process all the electrons and returns some back. These are then captured on oxygen and form very reactive superoxide O2- molecules. The SOD enzyme rapidly converts superoxide molecules in the presence of water to hydrogen peroxide H2O2. The latter is not so reactive and acts as a regulatory signal. It informs the cell that the fuel cannot be burned fast enough and it is necessary to somehow get rid of the excess energy, e.g. by producing fats or to obtain more oxygen and produce heat. And it is precisely for the production of heat that UCP enzymes are used. They act as controlled discharge circuits. It can also be compared to the release of steam from a boiler when heat is released. They reduce the voltage on the capacitor and thus reduce the formation of superoxide and hydrogen peroxide. It therefore acts similarly to antioxidants. Excessive production of H2O2 would lead to a switch to anaerobic metabolism and activation of HIF-1α, which is prevented by UCP2 activity.

But what happens in the arteries? If the flow is laminar, UCP2 production is increased, oxidative stress is reduced, and plaque does not form. Alternating mechanical stress, however, cancels this protection if there is an excess of energy in the endothelium, the resulting superoxide will damage the endothelium and vascular plaque will form. This is clearly seen in a model with the endothelial enzyme UCP2 selectively disabled (EC-Ucp2 KO).

And here we can ask the question, would acetate also help the cells of the vascular endothelium? Acetate also activates UCP2, as shown by a study on mice fed a high-fat diet supplemented with sodium acetate.

Effects of short fatty acids on enzyme activation and deactivation by AMPK (pAMPK) phosphorylation in liver cells. Note activation of UCP2 and deactivation of ACC (pACC).

Couldn't acetate solve not only obesity, but also Alzheimer's and cardiovascular problems? Maybe some study will show this, for now it's just hypothesis and speculation.

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References:

Short-Chain Fatty Acids Protect Against High-Fat Diet-Induced Obesity via a PPARγ-Dependent Switch From Lipogenesis to Fat Oxidation

Elevating acetyl-CoA levels reduces aspects of brain aging

Endothelial UCP2 Is a Mechanosensitive Suppressor of Atherosclerosis

Targeting the AMPK pathway for the treatment of Type 2 diabetes