Name: Eric Olson
Position: Professor and chairman, molecular biology, University of Texas Southwestern Medical Center
Background: Founder and consultant, Myogen — 1996
Professor/chairman, biochemistry/molecular biology, MD Anderson Cancer Center — 1991-1995
Associate professor, biochemistry/molecular biology, MD Anderson Cancer Center — 1989-1991
Assistant professor, biochemistry/molecular biology, MD Anderson Cancer Center — 1984-1989
Postdoc, biological chemistry, Washington University School of Medicine — 1981-1983
PhD, biochemistry, Bowman Grey School of Medicine, Wake Forest University — 1981
BA, chemistry/biology, Wake Forest University — 1977
In this week’s early edition of the Proceedings of the National Academy of Sciences, Eric Olson and colleagues from the University of Texas Southwestern Medical Center published data showing that a group of 12 microRNAs are involved in cardiac hypertrophy and heart failure. Importantly, one miRNA — miRNA-195 — was linked to pathological cardiac growth and heart failure in transgenic mice.
RNAi News spoke with Olson about the findings and his plans going forward.
Let’s start with a brief overview of your lab.
The main focus of my lab is to use muscle cells as a model to answer basic questions of development and gene regulation. So we study cardiac, skeletal, and smooth muscle cells; how the genes that establish those cell types are regulated during development; and recently we’ve also started to look at the mechanisms that go awry in various diseases of muscle tissues, in particular, the heart.
Heart failure is the number one cause of death and disability in the industrialized world. There are 5 million Americans with failing hearts and that number is increasing. So we’ve been trying to decipher the signaling mechanisms and genomic responses that occur in heart failure. We’ve made mouse models of heart failure and pathological cardiac enlargement, and have identified a large number of signaling pathways and genetic changes in that disease.
Given the recent work with microRNAs that suggested that they play a role in modulating growth, differentiation, and cellular phenotypes, we decided to ask whether microRNAs might play a role in adult heart diseases — that’s why we initiated this study [that appears in PNAS].
In the paper you focused on 12 microRNAs. How did you select those?
As a first step we decided to look at hearts from two different mouse models of cardiac hypertrophy and heart failure.
One is a genetic model that we created in our lab several years ago, in which we activated calcineurin — a calcium-sensitive phosphatase that is a powerful driver of cardiac hypertrophy and heart failure. We took [these] mice that had failing hearts due to calcineurin activation and compared them to normal [mice].
We also performed a surgical maneuver [in another group of mice] in which you can constrict the vessels that leave the heart, which forces the heart to pump against increased pressure mimicking hypertension, a potent stimulus for hypertrophy and heart failure.
We isolated RNA from [the hearts of the two sets of mice] and did a microRNA microarray [experiment] to look at 200 or so different microRNAs and ask, “Do any of these change in abundance under conditions of heart disease?” We found a collection of microRNAs that were regulated — some up-regulated and some down-regulated — in both models of cardiac disease. So we felt this was likely to be a signature, at least, of hypertrophy and heart failure — although at that point we didn’t know whether they were causally involved or just some secondary effect.
Once you had narrowed it down to these 12, what were the next steps?
We asked whether any of those [miRNAs] were also altered in their expression in failing human hearts, and several were. That suggested to us that we were on to something.
We put several of these into viruses and expressed them in heart muscle cells in the culture dish, and it was pretty reassuring that several of the microRNAs that were turned on in enlarged hearts in animals were sufficient to cause hypertrophy of cardiac myocytes in the tissue culture dish. So we felt that these were playing a role in the biology of the process, and selected a couple of these and expressed them in the hearts of transgenic mice. The remarkable finding was that one in particular, microRNA-195, was sufficient to induce cardiac hypertrophy and heart failure when we elevated its expression.
On its own?
On its own. So [the miRNAs are] not just a signature of heart disease. At least this one and maybe others are sufficient to evoke the disease process.
Did you also find that some of the other microRNAs needed to work in concert to result in hypertrophy?
That’s a good question. We haven’t yet done that. We’ve just looked at a couple of them singly in transgenic mice. As you can imagine, to make mice that are expressing multiple [miRNAs] takes a lot of breeding and such. We will go back and do that, but the fact that a single one [has such a great effect] is quite remarkable. Clearly that one, and maybe others, are sufficient to induce hypertrophy. Certainly in culture many of them were sufficient to induce hypertrophy.
We still need to test whether they are necessary to induce hypertrophy, and that is a little more complex. For that, we’re going to have to generate knockout mice lacking these microRNAs, and we’re well-along towards that right now.
What are some of the other next steps?
The other really important next step is to understand how these microRNAs are evoking these changes in the heart. Some of them, like microRNA-195, can cause hypertrophy while some other ones went down in the failing heart. When we misexpressed those in cultured heart muscle cells, they seemed to prevent cardiac growth. So they may almost be antagonists of cardiac growth and heart failure.
The key question to ask is, “What are the targets of these microRNAs that allow them to evoke these responses?”
Do you have any hunches at this point?
We’ve done a bunch of bioinformatics searches to look for predicted targets and we have found some we think look very interesting. But we have to validate those.
As you probably know, these microRNAs can select for targets with a large degree of degeneracy. It’s estimated that microRNAs can have dozens of targets, and trying to find the specific one or few that might be responsible for this phenotype is a challenge.
At this point, is this an in-house project or are you collaborating with other researchers from other institutions?
No. We’ve just done this ourselves here so far. We’re just following up on these and seeing where it goes.
Is this the first work for you looking at microRNAs?
No, this was our entrée into this field.
Do you plan on expanding into other muscle tissue and other projects in the lab?
Based on these results, which were very interesting, we have extended these studies into some other directions — for example looking at the role of microRNAs in skeletal muscle hypertrophy and in remodeling of the vascular system during disease.
Do you expect that some of the same microRNAs may be at play in the different tissues?
I think that’s going to be the case. Some of these microRNAs, and we already know this to be the case, are going to be involved in modulating muscle growth and function. Some are going to be, I think, playing a role as switches between cellular states. [For instance,] as a cell goes from growth to differentiation, there might be microRNAs that mediate that, and those will not necessarily be heart-specific. They may be operating in a number of tissues to cause those sorts of transitions.