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UT Southwestern Researchers Publish Link Between miRNA Dysregulation, Heart Attack

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NAME: Eric Olson
 
POSITION: Professor/chairman, molecular biology, UT Southwestern Medical Center
 
BACKGROUND:
— 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, Wake Forest University School of Medicine, 1981
 
NAME: Eva van Rooij
 
POSITION: Postdoc/instructor, UT Southwestern Medical Center
 
BACKGROUND:
— PhD, cardiology, University of Maastricht, 2004
— BA, medical biology, University of Maastricht, 2001
 
Last month, researchers from the University of Texas Southwestern Medical Center, in collaboration with microRNA-targeting drug developer Miragen Therapeutics, reported in The Proceedings of the National Academy of Sciences data demonstrating that acute myocardial infarction caused dysregulation of a specific set of miRNAs in humans and rodents.
 
One of those miRNAs, miR-29, was particularly associated with cardiac fibrosis, making it a potential target for therapeutic intervention, according to the paper.
 
This week, RNAi News spoke about the findings with two of the study’s co-authors, UT Southwestern Medical Center professor and Miragen co-founder Eric Olson and Eva van Rooij, a postdoc in Olson’s lab and adjunct director of research at Miragen.
 

 
Let’s start with some background to the PNAS paper, which builds off earlier work looking at microRNAs and cardiac hypertrophy and heart failure.
 
EO: By doing microRNA profiling, Eva showed in the previous paper that there is a specific pattern of microRNAs that are diagnostic for failing heart in both rodents and humans. Her subsequent work showed that they are not only diagnostic but many of those microRNAs are necessary and sufficient for aspects of heart disease.
 
In this paper, she tried to extend that work and ask if there are microRNAs that might also be involved in the response of the heart to a myocardial infarction.
 
What was the approach you took to studying the expression of microRNAs in that situation?
 
EvR: To look at microRNAs that are regulated in response to an infarct, we used a mouse model [in which] we can mimic an infarct. When we profiled our microRNAs, we divided the heart up into different sections because the infarct induces a different kind of stress right at the border zone of the infarct compared to the rest of the heart.
 
We mainly focused on the region that directly flanks the infarct because that is a very dynamic region, and we found a specific pattern of expression of microRNAs that was directly influencing the response to the infarct.
 
These microRNAs were different than those from the previous work with hypertrophy and heart failure?
 
EvR: There was overlap, but we also found specific microRNAs for post-myocardial infarction remodeling. The interesting thing for us is that we could confirm the expression of these microRNAs in human cardiac samples from people who suffered an infarct.
 
How significant was the overlap between the microRNAs?
 
EvR: There are several things going on in response to an infarct. Of course, you get the pathological remodeling as we could see in our previous study. Then you get microRNAs like microRNA-21 and microRNA-15, which we also saw before.
 
But, for instance, microRNA-29 we saw down-regulated in the diseased hearts before, but [in MI samples the down-regulation] was really striking. A very dominant aspect of post-MI remodeling is cardiac fibrosis, and although that is going on in the disease models we used for the previous paper, after an infarct this process is really very dominant.
 
We recognized [miR-29’s] importance from the previous study, but when we went into more detail about what it might possibly target or what kind of a process it might influence, it was very clear to us that it was influencing the onset of fibrosis.
 
Do you know what that microRNA’s role is in normal situations?
 
It’s expressed mainly in fibroblasts, and we think it is expressed to repress the expression of collagen-related genes [and] maintains the elasticity and flexibility of the cardiac tissue.
 
Following the infarct, did microRNAs levels return to normal or were they permanently dysregulated?
 
EvR: The strongest effects on the fibrotic-related microRNAs, like miR-29, we saw in the first week. But the secondary response, which is more of a hypertrophic response … we saw different microRNAs still being highly regulated.
 
Are there plans to follow up on these findings?
 
EvR: What we’re doing now is an additional study, which [involves] ischemia reperfusion. You give the heart a period of ischemia and then you reperfuse the vessels. That is actually what happens with patients who come into a hospital after they suffer an infarct — they are being reperfused. I can imagine that different microRNAs are going to be involved here.
 
The PNAS paper mentioned that miR-29 could be a therapeutic target. Where do you see the potential there? Specifically for treatments following a heart attack?
 
EvR: The [potential would be for enhancing the] initial fibrotic response you need for infarct healing after a myocardial infarction. But we could envision bringing this microRNA back into the system and thereby reducing the fibrosis that is not required for infarct healing and induces the stiffness after infarct.
 
EO: It’s also worth keeping in mind that that the application of the microRNA is likely to extend beyond myocardial infarction and have implications for lots of other human diseases that are associated with fibrosis such as liver fibrosis, kidney fibrosis, pulmonary fibrosis, and even wound healing.
 
Have you at all looked at the role of this microRNA outside of the heart?
 
EvR: That’s what we’re currently doing.
 
Is miR-29 one of the targets Miragen is looking at?
 
EvR: Yes. We are definitely looking at microRNA-29 in cardiac fibrosis because [the company’s] main focus is cardiovascular disease, but we’re extending that to the fields Eric was just pointing out.
 
EO: We think there are at least two reasonably straightforward therapeutic approaches that we could take to manipulate miR-29 and Miragen is keenly interested in those. One is to develop miR-29 mimics to elevate the expression of miR-29 in the setting of diseases that are associated with fibrosis.

The other would be to understand how the gene itself is regulated and then to develop small molecules or [other] pharmacological approaches that could stimulate the expression of the endogenous miR-29 in the setting of fibrosis.
 
There are several microRNAs that Eva has discovered that we are knocking down through antagomir approaches together with Miragen, and we have some very exciting data on that, but this would be an example of a microRNA [whose expression] we’d want to elevate.
 
What we envision ultimately is the development of microRNA cocktails. You can imagine delivering a combination of a [miRNA] mimic and an antagomir for different combinations of [miRNAs] in the setting of heart diseases or other diseases.
 
EvR: Like Eric said, specific microRNAs appear to regulate specific facets of the cardiac remodeling process. It’s very clear that miR-29 is involved in fibrosis, but we have a couple that are influencing myocyte hypertrophy and [one] that influences myocyte survival. Hopefully, we’ll eventually end up with a cocktail that will be an ideal therapeutic.

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