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Beyond Lipids: Understanding the Mechanics of Atherosclerosis

New research by Shu Chien helps explain why atherosclerotic lesions form at the branches of coronary arteries, work that could lead to new avenues of treatment for heart disease.
New research by Shu Chien helps explain why atherosclerotic lesions form at the branches of coronary arteries, work that could lead to new avenues of treatment for heart disease.

Atherosclerosis, the collection of deposits such as cholesterol along artery walls, accounts for nearly 75 percent of deaths from cardiovascular disease. Most drugs to treat atherosclerosis influence the levels of cholesterol and other blood lipids, but a group of UCSD researchers led by bioengineering professor Shu Chien is investigating the mechanical forces acting on blood vessels as a way to design better approaches to treatment.

Narrowing and hardening of coronary arteries typically appear first at vessel branches, and a study by Chien and his collaborators published in the October issue of Cellular Signalling shows that the type of mechanical stretching found at those branches activates a cellular protein known to damage cells.The report is the first to link mechanical forces with structural and biochemical changes in blood vessel cells that could explain why atherosclerotic lesions form at the branches of coronary arteries.

The cellular protein in question is called JNK, short for c-jun N-terminal kinase. It is a key barometer of outside stresses on a variety of cell types. Researchers are examining the role of JNK in many diseases because it regulates the expression of genes involved in programmed cell death, tumor genesis, and other stress responses.

“We’ve known for decades that atherosclerotic lesions develop preferentially at vessel branches rather than along unbranched vessels, but we’ve not been able to identify the biochemical events that trigger formation of the lesions,” said Chien, director of the Whitaker Institute of Biomedical Engineering at UCSD.“We now have identified a possible smoking gun: activation of JNK, which is dependent on the directionality of blood vessel stretching.”

Chien, along with research scientist Shunichi Usami and post-doctoral fellow Roland Kaunas, stretched endothelial cells 10 percent of their length 60 times per minute to simulate the rhythmic flexing of an artery in response to heart beats.

Cells that were stretched back and forth along one axis exhibited a healthy response: the level of JNK rose and quickly returned to basal levels as the cells also produced well-aligned intracellular actin fibers that were aligned perpendicular to the axis of stretch. When the researchers stretched cells in two directions simultaneously they noted an unhealthy response: actin fibers oriented randomly and JNK concentrations rose to higher levels and remained elevated.

“The actin cytoskeleton of endothelial cells is somehow playing a key role in activating and deactivating JNK,” said Chien.“Our new understanding of how mechanical forces affect JNK will eventually help us gain better understanding of the mechanism underlying the focal localization of atherosclerotic lesions and design better approaches to treat this important disease state.”

STRETCH EFFECT: UCSD bioengineers have found a link between parallel alignment of “stress fibers” in blood vessel cells and healthy levels in those cells of a protein called JNK.
STRETCH EFFECT: UCSD bioengineers have found a link between parallel alignment of “stress fibers” in blood vessel cells and healthy levels in those cells of a protein called JNK.