Drug target to prevent hardening of arteries identified

Washington: Researchers have come a step closer towards limiting arterioscelorosis disease - an illness in which hardening of arteries occurs and the supply of oxygen-rich blood throughout the body is squeezed off.

Scientists at the Sanford-Burnham Medical Research Institute have described the molecular and cellular pathway that leads to this hardening of the arteries-and zeroed in on a particularly destructive protein called Dkk1.

Dwight A. Towler, senior author of the study, said that he hopes to develop a therapeutic drug that would include a Dkk1 inhibitor and a peptide-a short chain of amino acids-engineered to target specific vascular tissues.

"I think the strategy going forward is to find ways to modulate or inhibit Dkk1 function, but we`re going to have to do it in a time-sensitive and cell type- specific fashion," Towler, M.D., Ph.D., director of Sanford-Burnham`s Cardiovascular Pathobiology Program, said.

"In diseases such as chronic renal deficiency or diabetes, where unregulated Dkk1 signaling can be destructive, it may be appropriate to restrain the action of Dkk1 for a prolonged period of time," Towler added.

The Dkk1 protein, when functioning normally, is important for aiding in wound repair. But inflammatory responses triggered inside artery walls after the onset of hyperglycemia, and other metabolic injuries associated with diseases like diabetes, can trigger prolonged and destructive Dkk1 signaling.

Dkk1 triggers the conversion of cells that line the interior surface of artery walls, called endothelial cells, into mesenchymal cells, which can direct connective tissue formation.

This process is known as the endothelial-mesenchymal transition. The resulting fibrosis inside arterial walls leads to a dangerous stiffening of vessels that increases systolic blood pressure and ultimately impairs distal blood flow.

Longtime Sanford-Burnham researcher and past president Erkki Ruoslahti, M.D., Ph.D., developed homing peptide s, which have been used to deliver cancer drugs to where they`re most needed.

The study was published online by Arteriosclerosis, Thrombosis, and Vascular Biology.