Atherosclerosis is an inflammatory condition. Oxidized lipids lead to the formation of fatty plaques that narrow and weaken blood vessels, the growth of those plaques driven by the activities of macrophages that try and fail to repair the damage. They become overwhelmed and die: plaques are a mix of fat and the cellular debris from dead macrophages. Prior to their destruction, macrophages generate inflammatory signaling as atherosclerosis worsens, but how is it that other sources of age-related chronic inflammation can accelerate the progression of atherosclerosis? Researchers here explore some of the less well-understood parts of the feedback loop between inflammation and mechanisms of atherosclerosis, in search of answers.
Investigators have identified a new cellular pathway that may help explain how arterial inflammation develops into atherosclerosis - deposits of cholesterol, fats, and other substances that create plaque, clog arteries, and promote heart attacks and stroke. "We have known for decades that atherosclerosis is a disease of chronic inflammation that ultimately results in the scarring of arteries and tissue damage. But the ongoing stimulus for this inflammation has been unclear."
A new study sheds light on this mystery by using a bacterial infection to reveal a cascade of cellular events that can lead to inflammation and atherosclerosis. Investigators focused on interleukin-1 beta, a type of protein that is assembled and released by immune system cells in response to infection and injury, including tissue damage caused by atherosclerosis. While interleukin-1 beta helps rally the immune system against these threats, it also can cause chronic inflammation. The study team wanted to understand how the interleukin-1 beta pathway might promote atherosclerosis.
To make its way out of the immune system cell, interleukin-1 beta can also use the same chemical channels that are used by cholesterol to exit the cell. The result is a "traffic rush" on those channels that blocks the exit of artery-damaging cholesterol and causes it to accumulate in the cell. Once it is released by the cell into the body, interleukin-1 beta suppresses a chemical receptor that enables niacin to be used in the body. This action is harmful because niacin works by removing cholesterol from cells in the artery walls. When niacin is blocked, cholesterol can accumulate in the walls. The suppression of the niacin receptor has another negative effect: It reduces the number of chemical channels that cholesterol uses to exit the immune system cell, causing more cholesterol to be trapped inside. That is because the niacin receptor, besides enabling niacin, also increases these channels as part of its normal function.
These discoveries are especially significant because drugs that inhibit interleukin-1 beta have shown promise in combating atherosclerosis and heart disease. A major clinical trial, led by another research institution and published last year, reported that administering one such drug to patients who had a prior heart attack reduced inflammation and lowered the risk of another cardiovascular event. The study raises the possibility that by using drugs to block the initial production of interleukin-1 beta, rather than just neutralizing it, a stronger positive effect could be obtained for these patients.