By Susan Gammon, Ph.D.
“We have identified several chemical modifiers that mimic LRP6 actions,” said senior study author Dwight A. Towler, M.D., Ph.D., adjunct professor in the Cardiovascular Pathobiology Program at SBP’s Lake Nona campus, and professor of Internal Medicine at UT Southwestern Medical Center. “Since these and other molecules are being developed for adjunctive cancer therapies, we may be able to repurpose these compounds or their derivatives for the treatment of diabetic arteriosclerosis, thereby reducing the risk of stroke, heart failure, lower extremity amputation, and potential renal failure. ”
Discovering a new player in vascular disease
Arteriosclerosis is a common disease in which cholesterol, calcium, and collagen build up inside the walls of arteries, leading to serious health problems, including stroke, heart attack, and risk of lower-extremity amputation. Arteriosclerosis increases with age, and the development of this disease is markedly accelerated in patients with diabetes. In a series of prior studies, Towler and his collaborators first identified that Wnt signaling cascades contribute to diet-induced hardening of the arteries in diabetic mice. Wnt proteins bind to a large family of receptors on the cell’s surface to regulate a variety of developmental and disease-related processes. However, different Wnt receptor combinations can trigger either prototypic (canonical) or non-classical (noncanonical) responses, and it has not been clear precisely which Wnt receptors control hardening of the arteries.
One clue to this question came from human genetic studies by others, which showed that an exceedingly rare mutation affecting one key Wnt receptor called LRP6 is associated with hereditary early onset cardiovascular disease. To further examine LRP6’s role in arterial disease, Towler and his collaborator Bart Williams, Ph.D., director of the Center for Cancer and Cell Biology at the Van Andel Research Institute, used genetic tools to specifically deplete LRP6 within the vascular smooth muscle tissue of mice predisposed to diet-induced diabetes and arteriosclerosis. They found that LRP6 depletion increased the stiffness of arteries by activating the noncanonical Wnt signaling pathways to promote vascular calcium buildup and bone-like tissue formation. “The findings reveal, for the first time, the importance of LRP6 in regulating the vascular smooth-muscle noncanonical signals that drive diabetes-induced arteriosclerosis,” Towler said.
An array of opportunities for drug development
In additional experiments designed to elucidate the noncanonical Wnt pathways controlled by LRP6, the researchers discovered that enzymes controlling protein arginine methylation are key components of the arteriosclerosis-related signaling cascade. “These results reveal novel dimensions of LRP6 vascular biology that provide insights useful for crafting new approaches to treating arteriosclerotic disease; this affords additional opportunities for small-molecule intervention, drug discovery and development,” Towler said. “Moreover, the effects of LRP6 depletion on these relays were reversed by compounds that block cdc42/Rac1 within the noncanonical Wnt cascade. We speculate that drugs targeting the cdc42/Rac1 family can function as partial LRP6 mimetics, and may prove useful in treating vascular disease in patients with diabetes,” Towler said.
In future studies, the researchers will continue to explore the entire spectrum of proteins altered by LRP6 to better understand how metabolic stressors such as diabetes can cause vascular smooth-muscle cells to morph into bone-forming cells. “We’re optimistic that these studies will uncover an array of signaling pathways that can be targeted by drugs to improve the outcomes of our patients afflicted with arteriosclerosis,” Towler said.
This story was written by Janelle Weaver, Ph.D., a freelance science writer.
The full paper can be found here.