You just ordered a triple cheeseburger with fries and chips? If you order this regularly, you are likely also ordering an eventual heart attack.

Consuming a lot of fat in your diet can lead to increased cholesterol levels. But cholesterol does not only come from what you eat, it is also synthesized by cells in your body with that synthesis often increasing with age depending on your genetic background. Cholesterol is not all bad, however, and it is required for certain vital functions. It forms the structural component of cell membranes and also is required for biosynthesis of steroid hormones, bile acids, and vitamin D.

As that cholesterol travels in the blood through your body, certain modifications occur to the molecules that can cause the modified form to stick to the arterial wall and form discrete plaques that can eventually clog your arteries. This is one reason why atherosclerosis is a chronic inflammatory disease.

Atherosclerosis is the major cause of cardiovascular disease, which is the leading cause of illness and death throughout the world. The economic cost of cardiovascular diseases for 2010 was $444 billion in the United States alone. This is a huge burden to the world for both economic and social reasons, and why researchers at the University of Toledo are focused on understanding the cellular processes involved to reduce the complications associated with atherosclerosis.

Initially, when modified cholesterol builds up and starts sticking to arteries, cells known as macrophages come to the site of cholesterol build-up and eat the modified cholesterol to help prevent plaque formation. In the early stages, macrophages are efficient in clearing the dying cells and modified cholesterol plaques.

But as time goes on, this process becomes defective. Similar to you eating too many cheeseburgers and fries over time, macrophages eating too much of the modified cholesterol is unhealthy for them. The work of incoming macrophages then increases because they now need to clear both the modified cholesterol and the dying macrophage.

As the plaque builds and more macrophages move in, specialized cells from the artery wall, called smooth muscle cells, form an elastic covering around the plaque in an effort to avoid rupture of the plaque into the arterial blood flow. However, at the same time, the dying macrophages start to leak their inner contents into the plaque. Those enzymes within the cellular contents can now dissolve that protective elastic layer, causing the plaque to break open into the arterial blood stream. This is what triggers the blood inside the artery to clot and results in blocking the arterial blood flow.

The process of atherosclerosis can be compared to pipelines (arteries) supplying water (blood) to different rooms (organs of the body such as the heart or brain) in your home. If the pipeline from the kitchen sink is blocked, your sink will not drain. Similarly, a blocked artery results in not enough blood to be supplied to the different areas of your body. If an artery supplying your brain is plugged, this will cause brain damage and a stroke.

The major problem with atherosclerosis is that it can remain undetected as the plaque grows larger. Arteries are elastic and can expand at the plaque site to maintain blood flow for a time. It is when the plaque causes too much arterial narrowing, choking off blood flow, that symptoms of pain first occur.

It has taken decades for scientists to understand the important role of macrophages in atherosclerosis. We now understand that macrophages are one of the major players in and contribute to many aspects of the disease.

At the University of Toledo college of medicine and life sciences, formerly the Medical College of Ohio, current research is focused on their role in another complication associated with atherosclerosis called vascular calcification caused by calcium deposits in the plaque that contributes to instability of the plaque. Vascular calcification is similar to bone formation and is a complicated process within the diseased arterial wall.

UT researchers are concentrated on understanding this process at both the cellular and molecular level. We know that cross-talk among cells within the arterial inner wall, smooth muscle cells, and macrophages drive this process.

A major project in our lab is to study the role of a protein complex in the macrophage’s membrane called Transient Receptor Potential Canonical Channel 3, known as TRPC3, in atherosclerosis.

We have performed cell culture experiments using macrophages that lack TRPC3 and have shown that these macrophages have a reduced expression of specific proteins that are key players in vascular calcification. We also observed reduced production of bone morphogenic protein 2 (BMP-2) in the medium in which the macrophages were cultured. BMP-2 is one of the key proteins causing calcification.

These initial results suggest that blocking TRPC3 in macrophages could reduce vascular calcification. We are in the process of confirming these results in animal models.

In the future, we hope to be able to contribute to the reduction of plaque buildup, vascular calcification, and plaque rupture, thereby decreasing cardiovascular diseases.

Prabhatchandra Dube is a Ph.D. student in the cardiovascular and metabolic disease track in the department of physiology and pharmacology at the University of Toledo college of medicine and life sciences biomedical science program. He is doing his research in the laboratory of Guillermo Vazquez. For information, contact Prabhatchandra.Dube@rockets.utoledo.edu or visit utoledo.edu/​med/​grad.

First Published January 4, 2016, 5:00 a.m.