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Sumeet Solanki 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.
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Heart Attacks: The view from inside your arteries

Heart Attacks: The view from inside your arteries

This is one in a series of articles written by research students in the University of Toledo college of medicine (the former Medical College of Ohio) Biomedical graduate program exploring basic issues of human health.

In the United States, someone has a heart attack every 34 seconds and someone dies from heart disease every 60 seconds. Heart attacks belong to a broader category of cardiovascular diseases and are the leading cause of death in the United States and worldwide.

Cardiovascular literally means heart and its blood vessels. Atherosclerosis is the usual culprit behind heart attacks.

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The process of atherosclerotic plaque formation in the arteries is very complex, although it is often regarded simply as a fat buildup in the innermost layer of cells in your blood vessel wall. In reality, atherosclerosis is a chronic inflammatory disease. Inflammation is the way that your body reacts to infections, or other foreign or harmful things.

So how does this all start?

Cholesterol is transported to and from cells within our body via two important particles, low density lipoprotein, or LDL, and high density lipoproteins, or HDL. LDL particles deliver cholesterol to cells and HDL removes cholesterol from cells. LDL is often regarded as “bad cholesterol” because increased levels contribute to atherosclerotic plaque formation while HDL is considered as “good cholesterol” because it reduces plaque formation. Foods that are high in fat can increase LDL-cholesterol particles in our blood and these tend to accumulate in the cell walls of our arteries, particularly our coronary arteries (arteries supplying blood to the heart).

Over time, these LDL-cholesterol particles undergo chemical and other modifications to become toxic, and are viewed as foreign by our body’s defense systems.

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Our body’s defense mechanisms try to remove these altered LDL-cholesterol particles accumulated within our arterial wall, similar to a defense against bacterial or viral invasion.

Macrophages are one of our important immune cells, form the first line of defense. Their job is to detect and remove all foreign invasive threats to the body and are the first ones to be recruited to the artery wall for clearing these toxic LDL-cholesterol particles. 

This process also recruits more macrophages to the damaged blood vessel wall. Macrophages, therefore, have been viewed as protective against toxic LDL-cholesterol particles in the past, but are now known to contribute to the development of dangerous plaques (which can rupture and cause heart attacks).

Research in the last decade has shed new light on many of the roles played by macrophages during the development of dangerous plaques. 

Unfortunately, during the process of clearing these toxic particles, macrophages become victims of this vicious cycle of unresolved inflammation. 

Macrophages in atherosclerotic plaques become overloaded with the toxic cholesterol and then die by a programmed cell death process called apoptosis. These apoptotic cells are recognized by surrounding healthy cells and are disposed of by a process called efferocytosis (eating of dead cells). 

However, in advanced atherosclerotic plaques, this eating of dead cells becomes defective. We are not sure why this happens.

So what happens to make these uneaten dead macrophages part of the problem?

Imagine what happens if the old leftovers in your refrigerator that you throw into the garbage are not disposed of properly. This waste decomposes, emitting foul odors and can eventually create a public health risk. 

Similarly, in advanced stages of atherosclerosis, dying macrophages are not efficiently disposed of properly and they start to decompose or become “necrotic.” The cell walls of necrotic macrophages break down, dumping their cellular contents into the plaque.

Many of these cell products are toxic outside of the cell and contribute to the development of highly dangerous unstable plaques. 

An unstable plaque will eventually rupture into the artery lumen, blocking the blood flow. This dramatic event can rapidly starve the heart of oxygen and nutrients within minutes, killing cardiac cells and producing a heart attack.

A main objective for many investigators in the field of atherosclerosis research is to identify proteins and mechanisms that control death of macrophages within plaques. Our research within the laboratory of Dr. Guillermo Vazquez at the University of Toledo College of Medicine and Life Sciences is focused on investigating the role of a specific protein called Transient Receptor Potential Canonical 3 (TRPC3). This protein forms channels — pores in the cell- that affects several cell functions. Studies from our laboratory suggest that TRPC3 alters a number of mechanisms associated with the death of macrophages.

By the use of cell culture experiments, we have found that when macrophages are exposed to cholesterol (to mimic the atherosclerotic plaque environment), TRPC3 channels activate specific proteins and initiate further signals known to be involved in the death of macrophages.

Remarkably, these death-signaling effects of TRPC3 can be prevented or reduced by using blockers of these channels. 

Thus these important research findings in our lab provide strong evidence that TRPC3 channels participate in death signaling in macrophages and further suggest that these channels may influence development and stability of atherosclerotic plaques. Current efforts in our laboratory are aimed at validating these findings in animal models of atherosclerosis. Therefore by understanding the role of macrophage TRPC3 in atherosclerosis, we might be able to prevent macrophages dying within plaques and prevent heart attacks.

Sumeet Solanki 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. Sumeet is doing his research in the laboratory of Dr. Guillermo Vazquez. For more information, contact Sumeet.solanki@rockets.utoledo.edu or go toutoledo.edu/​med/​grad/​biomedical.

First Published May 4, 2015, 4:00 a.m.

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Sumeet Solanki 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.
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