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Mariana J. Kaplan, MD
University of Michigan, Ann Arbor, MI
2002 Cardiovascular System
2002 Biomarkers
With LRI funding, Kaplan set out to investigate the mechanisms by which blood vessels are damaged in women with lupus and lead to premature vascular disease.
She found that some people with lupus appear to get premature atherosclerotic changes due to the rapid death and slow replacement of endothelial cells. These cells, which line the blood vessels and cavities of the heart, normally keep plaques and clots from forming.
“We found that the lupus patients had abnormal vascular function that was impaired to the same extent seen in the heart disease patients – despite the fact that the lupus patients were approximately half the age,” she explained.
Kaplan also contributed to a report that poor vascular function in people with lupus is associated with increased levels of a protein that regulates blood clotting.
Kaplan has shared results from her LRI-funded work at several international meetings, and is hopeful that her discoveries will lead to a biomarker to identify people with lupus at risk of cardiovascular disease. She also envisions designing therapies to prevent endothelial cell damage and thereby slash the risk for premature atherosclerosis.
Select publications:
Accelerated macrophage apoptosis induces autoantibody formation and organ damage in systemic lupus erythematosus. Denny MF, Chandaroy P, Killen PD, Caricchio R, Lewis EE, Richardson BC, Lee KD, Gavalchin J, Kaplan MJ. J Immunol. 2006 Feb 15;176(4):2095-104.
Plasminogen activator inhibitor-1 is associated with impaired endothelial function in women with systemic lupus erythematosus. Somers EC, Marder W, Kaplan MJ, Brook RD, McCune WJ. Ann N Y. Acad Sci. 2005 1051:271-80.
Apoptosis in systemic lupus erythematosus. Kaplan MJ. Clin Immunol. 2004 Sep; 112(3):210-8.
Endothelial cell apoptosis in systemic lupus erythematosus: a common pathway for abnormal vascular function and thrombosis propensity. Rajagopalan S, Somers EC, Brook RD, Kehrer C, Pfenninger D, Lewis E, Chakrabarti A, Richardson BC, Shelden E, McCune WJ, Kaplan MJ. Blood. 2004 103(10):3677-83.
Ongoing funding:
In 2005, Kaplan won $200,000 from the Alliance for Lupus Research grant to further research the findings she made through her LRI grant.
In the Lab
Young premenopausal women with lupus are significantly more at risk of heart disease and stroke than healthy young females. In fact, premature heart disease is the third most common cause of death in these patients, following complications of kidney disease and infection. Heart attacks in lupus patients occur in the majority of cases because of increased atherosclerosis, the development of hardened areas and narrowing in the blood vessels that carry oxygen to the heart. Traditional risk factors for atherosclerosis (smoking, high cholesterol, hypertension, diabetes) do not appear to explain this increased propensity, and it is believed that immune abnormalities present in lupus patients may be important contributors to this complication.
With a grant from the Lupus Research Institute's (LRI) Novel Research Program, Dr. Kaplan and collaborators at the University of Michigan Medical School, Ann Arbor, MI, are uncovering some of the detailed mechanisms by which lupus patients develop early heart disease and strokes, findings that may help to develop new treatments that reduce the risk of premature atherosclerosis.
Dr. Kaplan shares the significance of her findings in an interview with the LRI:
LRI: Can you describe your LRI-funded research project?
Dr. Kaplan: Damage to the linings of arteries is common among lupus patients. We are studying the phenomenon of dysfunctional and dying endothelial cells, which line the cavities of the heart and blood vessels, and are trying to understand the reasons for the breakdown and rapid death of these cells through a process known as apoptosis. The development of atherosclerosis and blood clots is hastened in the presence of apoptosis. We are measuring the loss of "elasticity" in blood vessels, the ability to enlarge in response to increased blood flow, as a way of determining the presence of damaged blood vessel linings. We also plan to look at whether the body's own mechanisms of repairing damaged blood vessels might be impaired in lupus.
LRI: What is the present state of your research?
Dr. Kaplan: We have completed the first phase of our study in which we compared 43 lupus patients with the same number of older patients with clogged heart arteries and healthy controls. Circulating endothelial cells were collected from each group and tested for evidence of apoptosis by different methods. Blood vessel endothelial function was measured by an ultrasound method that can detect changes in blood vessels of the arm in response to release of a blood pressure cuff. Abnormal blood vessel endothelial function is known to be a good predictor of future atherosclerosis development. We also evaluated whether individuals with lupus were producing higher levels of a substance that is known to induce clots, called tissue factor, whose activity is increased during apoptosis.
LRI: What have you discovered?
Dr. Kaplan: Because of lupus, women in their 30s had the vascular health of 65-year-olds with coronary artery disease. We found that the lupus patients had abnormal vascular function that was impaired to the same extent seen in the heart disease patients—despite the fact that the lupus patients were approximately half the age of the heart disease control patients. Even the heart patients had fewer dying endothelial cells in their blood than the lupus patients. The study suggests that lupus patients' heightened heart risk may be due to the rapid death and much-too-slow replacement of endothelial cells, which normally keep plaques and clots from forming in blood vessels. Even in the absence of other risk factors, women with lupus have a higher risk of dying young from cardiovascular events. We also found that the presence of endothelial cell apoptosis correlated with the levels of tissue factor. We believe that endothelial cell apoptosis could be an important mechanism in the generation of tissue factor and account in part for the increase in risk of blood clots in lupus patients, but more studies are needed to confirm this.
LRI: Can you explain the significance of your findings?
Dr. Kaplan: Our findings are important because endothelial dysfunction is a predictor of changes in the arteries that are related to future atherosclerotic heart disease. Previous research has shown that apoptotic cells stimulate increased production of clotting proteins in the blood, and we believe this may potentially contribute to the well-known tendency of lupus patients to form blood clots. Our results suggest that lupus patients' heightened risk for accelerated heart disease may be due, at least in part, to the death of the cells that normally prevent the formation of hardened areas and clots.
LRI: What is novel about your research?
Dr. Kaplan: Several laboratories are studying the role of endothelial cell apoptosis in patients without lupus but with atherosclerosis secondary to other risk factors (like high cholesterol and smoking). To our knowledge, our lab is the first one to uniquely focus on the role of endothelial cell apoptosis in early heart disease in lupus. We have now shown the correlation between the presence of these dying cells and the development of abnormal vessel function in lupus patients who have not developed any symptoms of heart disease. This suggests that endothelial cell damage starts to occur early during the course of the disease.
LRI: How do you think your findings will help to direct the future development of therapies?
Dr. Kaplan: We plan to initiate experiments that will help us identify the mechanisms by which apoptosis occurs in the endothelial cells of lupus patients, including the interactions of these cells with different cells of the immune system. Characterizing the ways by which endothelial cells get damaged and contribute to atherosclerosis and clot formation will provide important information that could potentially help design therapies to prevent endothelial cell damage. We also plan to evaluate how well the apoptotic endothelial cell test predicts actual incidence of atherosclerosis and other heart and vascular diseases in Lupus patients. We want to determine whether this test could be combined with measures of vascular function to predict an individual patient's risk. This may lead to individual preventive therapy for lupus patients, with drugs now used for people who have a high risk of heart disease due to other factors.
LRI: Why have you concentrated your research on lupus?
Dr. Kaplan: Lupus is an important cause of morbidity in young women. Approximately 80 percent of new cases of lupus develop among women in their childbearing years and the impact on their lives can be enormous. While there have been significant advances in understanding lupus, this is a very complex and heterogeneous disease, and we do not know what causes it. Furthermore, no new therapies have been approved in several decades and we are in desperate need of new and effective treatments with fewer side effects.
About Mariana J. Kaplan, MD
Dr. Kaplan is an assistant professor of internal medicine in the Division of Rheumatology at the University of Michigan in Ann Arbor, Michigan. She is an internist and a rheumatologist, and her research has focused on the role of abnormal interactions between antigen-presenting cells and T-cells in the pathogenesis of lupus, and in studying mechanisms that contribute to accelerated atherosclerosis in lupus.
