Netrin-1 as a Novel Target in Atherosclerosis from US Biological

A recent study has identified a new culprit that leads to atherosclerosis, the accumulation of fat and cholesterol that hardens into plaque and narrows arteries (1, 2). The research explains why cholesterol-laden, coronary artery disease-causing cells called macrophages, accumulate in artery plaques.
Atherosclerosis is a disease in which plaque builds up on the inside of arteries. Plaque is made up of fat, cholesterol, calcium, and other substances found in the blood. Over time, plaque hardens and narrows the arteries. The flow of oxygen-rich blood to your organs and other parts of your body is reduced. This can lead to serious problems, including heart attack, stroke, or even death.

Atherosclerosis can affect any artery in the body. The effect on three different artery types can be described as: 1) Coronary artery disease (CAD) occurs when plaque builds up in the coronary (heart) arteries, CAD is a leading cause of death in the United States; 2) Carotid artery disease happens when plaque builds up in the carotid arteries (the arteries that supply blood and oxygen to your brain); 3) Peripheral arterial disease (PAD) occurs when plaque builds up in the major arteries of the legs, arms, and pelvis.

Many factors raise the risk for atherosclerosis. Major risk factors include unhealthy cholesterol levels, high blood pressure, smoking, insulin resistance, diabetes, overweight or obesity, lack of physical activity, age, and a family history of early heart disease.? Atherosclerosis usually doesn’t cause signs and symptoms until it severely narrows or totally blocks an artery. Many people don’t know they have the disease until they have a medical emergency, such as a heart attack or stroke. Other signs and symptoms depend on which arteries are narrowed or blocked.

In this recent study, researchers show why macrophages remain in artery plaques leading to atherosclerosis. Netrin-1 promotes atherosclerosis by retaining macrophages in the artery wall. In fact, netrin-1 signals macrophages to stop migrating and as a result these cells accumulate within the plaque. In addition, study experiments show, genetically deleting netrin-1 can minimize atherosclerosis, reduce the level of macrophages in plaque and promote the migration of macrophages from plaques (3,4). In the study researchers used a fluorescent tracking technique to label and monitor the movement of macrophage cells in and out of plaques. This experiment showed how macrophages were immobilized and retained in plaque by netrin-1 expression and also demonstrated macrophage emigration from plaque after the deletion of netrin-1.

This study provides new clues to help reduce the amount of plaque in arteries and the threat of atherosclerosis, a major cause of mortality in Western countries. The development of a new strategy to diminish macrophage accumulation in plaque offers great promise to reducing the occurrence of fatal cardiac events.

This image of atherosclerotic plaque shows the accumulation of macrophages in red. The movement of these cholesterol-laden, coronary artery disease-causing cells in and out of artery plaque was tracked using green fluorescent beads which can be seen within the red-stained cells (1).

Reference

1. van Gils, J. M. et al., (2012) Nature Immunology 13, 136–143
2. NYU Langone Medical Center, Office of Communications & Public Affairs, January 9, 2012
3. Libby, P. & Aikawa, M. (2002) Nat. Med. 8; 1257-1262.
4. Khan, J. A. et al., Gene Therapy (2011) 18; 437-444.

Selected Netrin-Related Products from US Biological