Nature Article: MicroRNAs Hold Promise for Treating Blood Vessel Disease

A newly discovered mechanism controls whether muscle cells in blood vessels hasten the development of atherosclerosis, according to an article published in a recent edition of the journal Nature.

microRNAThe study focused on cells known as vascular smooth muscle cells, which form in layers around blood vessels and regulate blood pressure. The cells can remain high-growth precursor cells, or they can mature into functioning muscle cells. Maintaining a proper balance between the two types of cells is crucial to heart health. The cells also take part in vascular remodeling that averts the blockage of blood vessels that occurs in atherosclerosis.

Rochester scientists have shown that the transition of these cells from fast-proliferating stem cells to mature cells and back again is largely controlled by two proteins, myocardin and serum response factor (SRF). But how myocardin itself is controlled has remained a crucial question: When levels of myocardin decrease, as they do in vascular diseases like atherosclerosis, vascular smooth muscle cells no longer work normally and vessel walls thicken.

In the paper published recently in Nature, the team from Rochester and from the Gladstone Institute of Cardiovascular Disease in San Francisco found that two microRNAs – single-stranded molecules of RNA – are part of a molecular switch that determines the fate of these cells. The team discovered in a mouse model that two such molecules, miR-143 and miR-145, in partnership with myocardin, maintain the normal balance between mature vascular smooth muscle cells and their precursors.

“The finding that a microRNA controls levels of myocardin, the master regulator of vascular smooth muscle cell identity and function, forms the starting point in efforts to design new classes of treatment for vascular diseases that represent leading causes of death,” said Joseph M. Miano, Ph.D., associate professor at the Aab Cardiovascular Research Institute at the University of Rochester Medical Center and a study author.

“One of the most important potential applications for this work would be to deliver miR-145 into vessel walls as a way to normalize levels of myocardin, which would counter vessel wall thickening,” added Miano.

Miano and the lead author of the study, Deepak Srivastava, M.D., director of the Gladstone Institute of Cardiovascular Disease, trained together under the direction of renowned muscle biologist Eric Olson at M.D. Anderson Cancer Center in the early 1990s. The current work was funded by the National Institutes of Health.

Miano and other Rochester colleagues have also found that myocardin and SRF activate genes that may influence the rate at which the brain can remove amyloid beta in patients with Alzheimer’s disease. In a February 2009 article in the journal Nature Cell Biology, Miano and Berislav Zlokovic, M.D., Ph.D., found that when SRF and myocardin are active, amyloid beta accumulates in smooth muscle cells lining blood vessels. The discovery that miR-145 encourages the expression of myocardin could explain why myocardin may occur in higher levels in Alzheimer’s disease.