But the Georgetown scientists also demonstrated that this stress-induced atherosclerosis could be prevented by blocking a certain neuropeptide in blood vessels. They say the results, published in the October issue of the American Heart Association journal Arteriosclerosis, Thrombosis and Vascular Biology, may someday lead to targeted therapy for individuals at risk for the condition.
The study is the newest in a series of animal studies that shows how chronic stress can be a high risk factor for accelerated atherosclerosis, a heart condition where plaque-like substances build up in the inner lining of an artery and can lead to heart attack or stroke. The study showed that the effects of stress were more rapid than the effects of a fat-rich diet in causing atherosclerosis.
"Stress is a newly emerging risk factor for cardiovascular disease but until now, we didn't know the exact mechanism involved," said Zofia Zukowska, MD, PhD, Professor of Physiology and Biophysics at Georgetown University Medical Center. "This research provides the first well-documented, experimental evidence in animals that stress can actually induce triggers that lead to vessel blockage and atherosclerosis."
In the study, researchers performed an angioplasty procedure on two groups of rats, and then induced stress in the experimental group. Follow-up tests carried out after just two weeks of daily stress showed that this stress significantly increased blood pressure and doubled circulating levels of neuropeptide Y (NPY) compared to rats that did not undergo stress. NPY is a neurotransmitter present in the nerves surrounding blood vessels which become activated by stress. Stress-activated nerves then release NPY onto the cells within the vessel wall, where it exerts several potent actions.
Previously, researchers knew that NPY could cause acute narrowing of the vessel by contraction of its muscular wall. However, this study showed that it has even more profound effects when it its levels are elevated chronically. In stressed rats which underwent angioplasty, NPY stimulated growth of abnormal smooth muscle in the blood vessels and caused them to become blocked with lesions containing microphages, thrombus and lipid deposits. These lesions resembled plaques which develop in humans in a process of atherosclerosis and are the cause of vessel blocking after angioplasty. This process has never before been reproduced in normal laboratory animals, unless they were genetically manipulated or were fed a fat-rich diet.
Researchers also found that it was possible to reverse this process by giving rats a compound that prevented cells from reading the increased levels of NPY. This compound, called the Y1 receptor antagonist, completely prevented the NPY-induced changes, allowing rats to undergo stress without increasing risk for atherosclerosis.
"This research has great potential for clinical applications in the future," said Zukowska. "Although this needs more study, if this same phenomenon occurs in humans, it is possible that Y1 antagonist could be used as a therapy for at-risk individuals."
Zukowska noted that if validated in humans, the research could be particularly applicable to men, whose bodies release more NPY during stress and who are generally more susceptible to heart attacks than pre-menopausal women. The findings also may prove helpful for individuals with mutations in the NPY gene, which occurs in some ethnic populations in as high as 9 percent of people, and which causes nerves to release the neurotransmitter in elevated levels.
Other co-authors on the paper include Lijun Li, PhD, and Ken Abe, MS, from Georgetown University and Anne-Catherine Jonsson-Rylander, PhD of AstraZeneca, Sweden, the company which provided Y1 receptor antagonist.
Georgetown's Biomedical Graduate Research Organization (BGRO) was created to foster cutting-edge, interdisciplinary collaboration and to enhance the university's research capacity, especially in the areas of child and human health and development, the neurosciences, cardiovascular-kidney health, and in shared work with researchers and clinicians from Georgetown's Lombardi Comprehensive Cancer Center. BGRO is also focused on educational and academic excellence in the biomedical sciences in order to train the next generation of scientific researchers in the United States and around the world.
Georgetown University Medical Center is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through our partnership with MedStar Health). Our mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis--or "care of the whole person." The Medical Center includes the School of Medicine and the School of Nursing and Health Studies, both nationally ranked, and the world-renowned Lombardi Comprehensive Cancer Center.