microRNAs role in CV disease

Researchers at the Gladstone Institute of Cardiovascular Disease (GICD) in San Francisco have discovered that two microRNAs regulate genes responsible for reverting vascular smooth muscle cells (VSMCs) from their mature to their high-growth precursor form.

The discovery has implications particularly for our understanding of the causes of the cardiovascular disease, atherosclerosis, and Alzheimer's disease, and could lead to improved methods of diagnosis and treatment.

MicroRNAs (miRNAs) are small molecules of RNA that are encoded by genes, but which don't translate into proteins. Instead they downregulate gene expression. They were discovered in the Victor Ambros lab in 1993.

This study, led by Deepak Srivastava, M.D, director of GICD, discovered two miRNAs, miR-143 and miR-145, which control VSMC differentiation and growth.

VSMC form in layers around blood vessels and control blood pressure by contracting or relaxing. They also grow and adapt as blood vessels change or become clogged by atherosclerosis. However, in order to grow, the VSMC must revert from their 'mature' state to their high-growth precursor stem cell form.

Past studies in Rochester have shown that transition of VSMCs from fast-proliferating stem cells to mature cells and back is largely controlled by two proteins, myocardin and serum response factor (SRF), as part of a regulatory network that influences many genes.

In this study, the researchers found miR-143 blocked the expression of factors that promote proliferation by VSMC precursors. Surprisingly, miR-145 activated the expression of myocardin, which maintains VSMCs in their mature form over their high-growth form.

In a mouse model, expression of miR-143 and miR-145 was reduced to almost nothing where disease-related proliferation of VSMC had thickened blood vessel walls.

These findings suggest that miR-143 and miR-145 - in partnership with myocardin - maintain the normal balance between mature VSMC and their precursors. Thus, researchers believe the drop in miR-143 and miR-145 levels seen in disease settings contributes greatly to vessel wall thickening, but that theory will need to be confirmed by further studies.

"The finding that a microRNA controls levels of myocardin, the master regulator of VSMC 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 Dr Joseph M. Miano, associate professor within the Aab Cardiovascular Research Institute at the University of Rochester Medical Center, and a study author.

"One of the most important of potential applications for this work would be to deliver miR-145 into vessel walls as a way to normalise levels of myocardin, which would counter vessel wall thickening," he said.

"There is a rising tide of interest in nucleic acid-based therapies, and a recent addition to our toolbox is the intriguing world of miRNA," said Professor Levon Khachigian, Director of the UNSW Centre for Vascular Research in Sydney.

"The explosion in academic and industrial interest in miRNA is based on the dissection of yet another level of gene regulation, and the great interventional potential of miRNA to correct the dysregulation of abnormally expressed and disease-causing genes," said Khachigian.

"miRNAs play an essential role during heart development and disease, examples including cardiac hypertrophy, dilated cardiomyopathy and heart failure. This new study deepens our understanding into blood vessels and expands the potential of microRNA as diagnostic and prognostic tools."

The study was published today in the journal, Nature.