A collaborative research effort at Pelisyonkis Langone has uncovered new evidence for a critical interaction between platelets and endothelial cells that could be an important accelerator in the pathogenesis of premature atherosclerotic disease in patients with lupus.
Cardiologist and senior author Jeffrey S. Berger, MD, associate professor of medicine and surgery, and rheumatology researcher, Robert M. Clancy, PhD, associate professor of medicine, say researchers have been trying to round up the major players that contribute to this critical lupus co-morbidity.
A past collaboration with Harmony R. Reynolds, MD, associate professor of medicine and associate director of the Cardiovascular Clinical Research Center, confirmed the phenomenon of accelerated atherosclerosis in both Caucasian and minority populations of lupus patients. Importantly, lab measurements linked Dr. Reynolds’s clinical assessment of cardiovascular disease to an endothelial disorder. The specific factors contributing to the lupus-atherosclerosis association remained unknown.
Illuminating the Role of Activated Platelets
The new study, published in the journal Arteriosclerosis, Thrombosis, and Vascular Biology, highlights the poorly understood role of activated platelets in accelerating the disease process and clarifies how they associate with endothelial cells. In particular, an RNA microarray of normal human umbilical vein endothelial cells co-incubated with platelets from patients with systemic lupus erythematosus (SLE) revealed an abnormal platelet-mediated effect on gene pathways involved in endothelial cell activation. By contrast, the co-incubation of platelets from healthy volunteers and human umbilical vein endothelial cells resulted in endothelial cells at a quiescent state similar to that of baseline endothelial cells.
“Moreover, we were able to identify that the platelets from lupus patients are releasing interleukin-1 beta, which is normally not present in healthy subjects,” Dr. Clancy says. “So we identified not only a pathogenic axis of platelet and endothelial cells, but also the mediator that the platelets were releasing to cause a phenotype of the endothelial cells, which resembles the process in atherosclerosis.”
Because lupus patients can have chronic production of IL-1 beta from platelets in their blood vessels, the research suggests that the triggered endothelium could take on atherosclerosis-like phenotypes. Beyond the upregulation of pro-inflammatory surface markers, Dr. Clancy adds, endothelial cells activated by platelets in vitro begin processing lipids abnormally compared with untreated endothelial cells.
Study co-author Jill P. Buyon, MD, says the research project arose from efforts of the Division of Rheumatology to investigate co-morbidities in lupus patients and pursue partnerships with other medical disciplines. Dr. Berger, a cardiologist who specializes in platelet research, helped the team uncover the previously hidden platelet-endothelial links.
“That interdisciplinary vantage allowed us to think about how endothelial cells and platelets, which hadn’t been well studied in lupus, might augment the risk of cardiovascular morbidities in SLE patients,” Dr. Buyon says.
A Collaborative Search for SLE Platelet Activators
To better understand the underlying mechanism, a follow-up collaboration among the Berger, Buyon, and Clancy laboratories is asking what factors may be activating platelets in lupus. So far, the research has identified a key player, an Fc receptor on the platelet surface that binds immune complexes, a component of protective immunity. These immune complexes, normally only transiently produced and then cleared away, persist in elevated levels in lupus patients.
The team’s emerging research is suggesting that a genetic variant of the Fc receptor, in which a histidine has been changed to an arginine, yields a highly reactive form of the receptor. The latter form, present in 40 percent of the U.S. population, interacts aggressively with immune complexes, potentially further delaying their clearance and activating platelets.
“If we can get supportive data, it would have great implications in identifying risk for accelerated atherosclerosis because tests for this genetic condition are widely available,” Dr. Clancy says.
The research is converging on an important clinical message, he adds: “If you are a lupus patient, and you have persistently circulating immune complexes, and you have the variant form of this protein, you are at higher risk.”
Dr. Clancy says the implications could extend far beyond atherosclerosis as well, given that blood vessel properties can influence blood flow to the kidneys and other important physiological functions. The continued collaboration, then, could help clinicians identify a wider pool of at-risk patients and enable earlier interventions.