In my last article "The Truth About Heart Disease Part I: The Story of Cholesterol", I talked about the role of LDL particles in heart disease. But, we still haven't gotten to the true cause of this whole process endothelial dysfunction. What is Endothelial dysfunction?Endothelial dysfunction is generally considered to be at the center of what triggers the cascade that...
In my last article “The Truth About Heart Disease Part I: The Story of Cholesterol”, I talked about the role of LDL particles in heart disease. But, we still haven’t gotten to the true cause of this whole process – endothelial dysfunction.
What is Endothelial dysfunction?
Endothelial dysfunction is generally considered to be at the center of what triggers the cascade that leads to the formation of a plaque. Endothelial cells (ECs) are the cells that form the internal lining of our blood vessels. But, they do much more than just sit there lining our arteries. Endothelial cells are very interactive with their environment and sensitive to changes in that environment – changes in blood pressure, oxidative stress and hormone levels among other things.
Similarly, ECs produce several substances that affect their environment in return. They produce nitric oxide (NO) which relaxes and opens blood vessels as well as chemicals, such as endothelin-1, that constrict blood vessels. They also produce adhesion molecules which cause white blood cells to “stick” to them and chemicals that can promote or prevent blood clotting.
What are the Root Causes of Endothelial dysfunction?
Endothelial dysfunction generally refers to an undesirable state where the production or availability of nitric oxide is low and/or the levels of other chemicals that constrict blood vessels, such as endothelin-1, are relatively high. Endothelial dysfunction is also associated with a state of EC “activation” where endothelial cells promote inflammation and blood clotting. In other words, endothelial dysfunction is a chronic state of vascular constriction and inflammation. So, what causes endothelial dysfunction?
To more clearly explain this, a little biochemistry jargon will be necessary. So, before I get there, let’s do a little tutorial on cell receptors. Every cell in our body has receptors. They are commonly found in or on the cell membrane – the fence that separates the inside of the cell from the outside. Many receptors are actually trans-membrane receptors, meaning they have a part that sticks outside of the cell and a part found inside the cell. Receptors are generally made of proteins, at least in part, and they allow cells to interact with the outside environment.
A commonly used analogy for how this works is a lock and key mechanism. The key may be a hormone that fits a specific receptor, the lock. When the key goes into the lock – or the hormone binds to the receptor – a certain action will occur. Sometimes receptors are quite specific and will only bind to one molecule – or one group of very similar molecules – while other receptors are more non-specific and will bind to many different types of molecules.
Generally, when a receptor binds to something, it will change shape. This is known as a conformational change. When this happens, it triggers an event inside the cell – an example of which would be the production of a signaling molecule. This will then often trigger a cascade of enzymatic activity leading to one or a number of specific outcomes. The outcome(s) could be anything from the release of a hormone to production of a new protein to the death of the cell and anything in between.
An important thing to remember is that when a specific receptor gets activated – by binding to a certain molecule – it always has the same response when found on the same type of cell. It doesn’t matter if it was activated by a hormone or a drug, the response is the same. To get different responses to the same substance, cells will use different receptors.
The Impact of LOX-1:
So, back to our main discussion, in the case of endothelial dysfunction, one of the primary receptors involved is known as lectin-like oxidized low-density lipoprotein receptor-1 or LOX-1. LOX-1 can be found on several types of cells, but for this discussion, we’ll be referring the LOX-1 receptor found on endothelial cells.
LOX-1 has a number of different outcomes when it is activated – one of the most important being the production of a substance that attracts white blood cells, specifically macrophages. This is one of the ways by which activation of LOX-1 can lead to inflammation. Activation of LOX-1 can also lead to the death of the endothelial cell, leading to injury to the blood vessel and further inflammation. LOX-1 can also trigger the production of reactive oxygen species (ROS), which if you remember from my last article, can lead to oxidized LDL particles.
You may now be wondering what activates or binds to LOX-1? Good question. LOX-1 can be activated by a number of things, including damaged cells, activated platelets, advanced glycation end products (found in diabetes) and bacteria & viruses. Most importantly, however, you may have guessed that LOX-1 can be activated by oxidized LDL particles.
It’s also important to consider what can increase the number of LOX-1 receptors found on endothelial cells. After all, if we have more LOX-1 receptors, there will be more opportunity for LOX-1 receptor activation and therefore more endothelial dysfunction. An increased number of LOX-1 receptors can be caused by inflammation, oxidized LDL particles, high blood pressure, omega-6 fatty acids, high cholesterol, obesity and diabetes.
You may have noticed that some of the causes of an increased number of LOX-1 receptors are products derived from the activation of LOX-1 itself. This can lead to a vicious cycle of endothelial dysfunction that could potentially end with the full blockage of an artery. For more detailed information on endothelial dysfunction and many of the involved mechanisms, go here.
The Contribution of Oxidation to Heart Disease:
If there is a theme to be seen in these last two articles, it’s oxidation. While oxidation may not be the only cause of heart disease, it is certainly one of the primary contributors. As mentioned in the previous article, oxidation is caused by reactive oxygen species (ROS). ROS are a natural by-product of the everyday metabolic processes in our cells. Some of the more common ROS include superoxide, hydrogen peroxide, hydroxyl radicals, nitric oxide and hypochlorous acid.
When ROS react with other molecules such as proteins and fats, it leads to damaged, dysfunctional cellular components and inflammation. While ROS naturally occur in the body, their levels can be increased by heavy metal toxicity, environmental toxins, sleep apnea and hemochromatosis (excess iron in the body) among other things.
Luckily, our cells have enzymatic antioxidants that can help protect us from ROS. Some of these antioxidants include superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase. We also get a number of nutritive antioxidants from our diet. These include vitamin C, vitamin E and beta-carotene as well as polyphenols such as flavonoids. Ideally, both the enzymatic and nutritive antioxidants work together to prevent ROS from causing any damage.
Unfortunately, however, a number of things can prevent this from happening and lead to what’s known as oxidative stress. Oxidative stress occurs when the balance between ROS and antioxidants favors ROS. Oxidative stress can occur when a diet is low in nutritive antioxidants, when enzymatic antioxidants are suppressed or when any of the previously mentioned factors increase the number of ROS beyond our antioxidant system’s capacity to handle. Oxidative stress has been implicated in a number of different disease processes, just one of which is heart disease.
Can we nail down the causes of Heart Disease?
So, what is the actual cause of heart disease? Unfortunately, there is no one right answer. Endothelial dysfunction is certainly at the heart of the matter (pun intended), but doesn’t happen by itself. While oxidative stress is often the cause of endothelial dysfunction, it’s not the only cause. Heart disease is a multifactorial process that involves dietary habits, level of physical activity, stress levels, environmental toxins (including cigarette smoke), obesity, diabetes, age and genetics.
In my next article, I’ll discuss some risk factors and tests for heart disease you may not be familiar with, but should be!