S100A1 protein critical for endothelial cell function in ischemic angiogenesis

Restoring diminished levels of a protein shown to prevent and reverse heart failure damage could also have therapeutic applications for patients with critical limb ischemia (CLI), suggests a new preclinical study published on-line October 9 in Circulation Research from researchers at the Center for Translational Medicine at Thomas Jefferson University.

Low levels of the protein S100A1 have been linked to congestive heart failure and high blood pressure, and now appear to be associated with critical lower limb ischemia, a condition found in type 2 diabetic patients where blood flow to legs is cut off, often resulting in amputation.

Past studies have shown that returning the protein to normal levels or above prevented and/or reversed congestive heart failure in massive animal models with gene therapy. Given these new findings, the researchers posit that S100A1 could also be a potential therapeutic target in CLI to promote revascularization.

The team was led by Patrick Most, M.D., adjunct Assistant Professor of Medicine at Thomas Jefferson University, and lead author of the study who now heads the Center for Molecular and Translational Cardiology at the University of Heidelberg, Germany, and Karsten Peppel, Ph.D., an Associate Professor in the Center for Translational Medicine at Jefferson and senior author of the study.

“In patients with CLI, this protein appears to be reduced to extremely low levels, nearly non-existent,” stated Dr. Peppel. “This dovetails with a finding we had when we were looking at patients with heart failure. We already know this protein has an important role in heart muscle cells. In patients who experience heart failure, there was reduced amount of the protein, down to about 40 percent of normal. Here, we showed in mice with CLI a similar defect in vascular cells and the inability to re-vascularize following arterial occlusion.”

Without successful revascularization, up to 40 percent of patients with CLI require major limb amputations within a year of diagnosis. CLI has many of the same predisposing risk factors as arteriosclerosis, such as smoking, high blood pressure and Type 2 diabetes. According to the American Diabetes Association, there are over 65,000 lower limb amputations performed in the United States a year as a direct result of diabetes.

“Understanding the fundamentals of disease mechanisms is key to finding better therapies. This actually exceeds the capacity of one laboratory,” stated Dr. Most. “Our integrative model of sharing expertise and resources between our laboratories in the U.S. and Germany has proven to be quite successful over the last years.”

Dr. Most’s laboratory has been working on S100A1′s role in heart disease for more than a decade, and together with a group from the Center for Translational Medicine at Jefferson, they have proven that loss of the protein causes diseased hearts to fail and that the protein is a potential target for gene therapy for heart failure.

S100A1, part of a bigger family of proteins called S100, is primarily found at high levels in muscle, particularly the heart. Falling levels of S100A1 are critical in the loss of heart-pumping strength after a heart attack and play an important role in the progression to heart failure.

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Submited at Thursday, October 11th, 2012 at 8:15 am on Uncategorized by Alina
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