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Increases in an Inflammatory Protein Leads to Heart Disease

An inflammatory protein, calprotectin, links hyperglycemia to myelopoiesis and the increase risk of coronary heart disease….

Atherosclerosis, a long term macrovascular complication of diabetes, has been recently linked to an inflammatory mediator protein. A collaborative research effort out of the Columbia University Medical Center, New York University and University of Pittsburgh has found the protein, calprotectin, as a key component in stimulating the inflammatory response that promotes the growth of the atherogenic plaque.

The study found an increase in inflammatory leukocytes in type 1 diabetic mice. During periods of hyperglycemia, elevated levels of circulating neutrophils and monocytes were measured. The researchers detected an increased production of calprotectin (S100A8/S100A9) from these neutrophils. Calprotectin is a complex of two calcium-binding proteins in which high levels have been seen in various inflammatory conditions, such as rheumatoid arthritis or cystic fibrosis. In the hyperglycemic state, high levels of calprotectin binds to the receptor for advanced glycation end products (RAGE receptor) leading to increased blood cell production from the bone marrow. The increased production and circulation of neutrophils during this inflammatory response continues to promote atherogenic plaque growth.

When these mice were treated for hyperglycemia, the researchers noticed the decreased production of neutrophils and monocytes, a reduction of the inflammatory response, and an overall regression of the atherosclerotic lesion.

The results of these findings in mice have a clinical implication in humans. Author and research Andrew J. Murphy said, "The human data appear to fit with the animal data, in that both WBCs and calprotectin are associated with heart disease." Two hundred ninety patients from the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study were analyzed. From the analysis of blood samples in patients with type 1 diabetes, plasma calprotectin levels positively correlated with elevated leukocyte counts and coronary artery disease.

The study co-author Alan R. Tall, MD, concluded, "Our findings point to the importance of controlling blood levels to limit the production of inflammatory cells that drive atherosclerosis; they also suggest novel therapeutic strategies, such as inhibiting the production of calprotectin or preventing its binding to the RAGE receptor."

Columbia University, News Release

Prabhakara R. Nagareddy, Andrew J. Murphy, Roslynn et al,."Hyperglycemia Promotes Myelopoiesis and Impairs the Resolution of Atherosclerosis" Cell Metabolism", Volume 17, Issue 5, 7 May 2013, Pages 695–708 http://dx.doi.org/10.1016/j.cmet.2013.04.001