Effects of oxidative stress on atherosclerosis

Heart disease and stroke are the first and third leading causes of death among men and women in the United States and account for 40 percent of all mortalities, according to the Centers for Disease Control and Prevention.

Studies show that high blood cholesterol—specifically a high level of low-density lipoproteins (LDL)—can put an individual at risk for cardiovascular disease by aiding in the formation of plaque along the artery walls, which is called atherosclerosis.

Plaques can grow large enough to cut off the blood flow, yet most of the damage occurs when they rupture and form blood clots. These blood clots either contribute to artery blockage or break off and travel to the heart or brain, which can trigger a heart attack or stroke.

"High levels of LDL are not the sole predictor for cardiovascular disease," said Alex Sevanian, Ph.D., professor of molecular pharmacology and toxicology at the USC School of Pharmacy. "Oxidative stress plays a critical role in the formation of plaques, and along with inherent vascular inflammation, may be a strong predictor of atherosclerosis."

For much of his career, Sevanian has worked to identify specific mechanisms that are responsible for atherosclerosis, to enable drug discovery experts to create therapeutic interventions. A sizable portion of his research has focused on the role that oxidative stress plays in the progression of cardiovascular disease. (deck)

Oxidative stress is a harmful condition that occurs when there is an excess of free radicals. Free radicals are formed when oxygen interacts with certain molecules and starts a chain reaction of damage among important cellular components. "Inflammation and the oxidative process are interconnected," said Sevanian. "Inflamed cells produce free radicals, which are involved in cell degradation."

"Within an inflamed vascular setting, LDL becomes oxidized and no longer behaves normally, he said. "It contributes to atherosclerosis by triggering more inflammation, disrupting normal vascular cell functions and resulting in the accumulation of plaque."

Sevanian and his colleagues have found that endothelial cells that make up the lining of vessel walls can be more easily activated to produce oxidants and other radicals, depending on the natural flow pattern of the blood stream.

"Areas of the vascular system with curves or forks (where flow is turbulent) are more likely to develop atherosclerotic plaques than are vascular areas with straight, unidirectional or non-turbulent blood flow," he said. “With high LDL, the likelihood increases for oxidation at areas of turbulence. The oxidized LDL becomes 'sticky,' which increases its interaction with endothelial cells that are more actively producing radicals. This further modifies the LDL particle and produces components that stimulate inflammation and abnormal behavior of the vessel wall. There is a prevalence of plaque formation in these areas."

Sevanian's group recently found that estrogen and some estrogenic compounds prevent the production of radicals by endothelial cells experiencing turbulent flow conditions, and enhance the tolerance of vascular cells to oxidative stress. They are presently working to identify the molecules within oxidized LDL that contribute to atherosclerosis—and determine which steps of the atherosclerotic process they affect.

Sevanian states "identification of the specific molecular sites where estrogen acts to prevent atherogenesis provides us with targets for medical intervention using more precise drugs."

"Soy components, which have estrogenic properties, bind to the LDL and prevent it from becoming oxidized," he said. "Preliminary work indicates that soy can slow the progression of atherosclerosis without estrogen’s potentially harmful side effects. Some of the cellular mechanisms affected by soy components are similar to estrogen’s and provide important focal points for further interventional studies."

Sevanian is currently collaborating on the new Women's Isoflavone Soy Health (WISH) clinical trial with Howard Hodis, M.D., professor of preventive medicine at the USC Keck School of Medicine and the Department of Molecular Pharmacology and Toxicology at the USC School of Pharmacy. WISH is the first randomized, double-blind, long-term study on soy protein isoflavones and their effects on vascular disease among postmenopausal women.

"WISH will have a tremendous impact on the clinical use of soy as a prevention method," Sevanian said, "and could pave the way to better targeted pharmaceutical agents that prevent atherosclerosis."

http://www.usc.edu/

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