|A/Prof Judy de Haan has won a five-year|
Baker Institute fellowship
by Anne Crawford
Dietary antioxidants have captured the popular imagination as being necessary for good health but their benefit in fighting disease is still uncertain. Associate Professor Judy de Haan has devoted her career to studying the oxidative stress that antioxidants counter and says the answers are more complex than vitamins.
Associate Professor de Haan, who heads the Oxidative Stress Laboratory at the Baker Heart and Diabetes Institute and holds an Honorary position at CCS, was recently awarded a five-year Baker Fellowship. She brings us up-to-date with the lab’s investigations and future research directions the Fellowship will support.
What is oxidative stress?
The body has ways to cope with an overproduction of oxygen-driven free radicals that occur naturally but which can cause different types of diseases and accelerate the ageing process. Our bodies have antioxidant defences endogenously but we can also take exogenous dietary antioxidants, a way of keeping the production of these free radicals under check. If overproduction of free radicals occurs, the body goes into a state of oxidative stress.
What can that lead to in terms of conditions or diseases?
These radicals are highly reactive so they can interact with molecules such as DNA, proteins and lipids. You then get an alteration in the structure of these important molecules which then affects organelles, cells and the organism in general, leading to disease. Oxidative stress is implicated in diseases such as Alzheimer’s disease and cancers, and in the area we’re particularly interested in – diabetic complications. We know it plays an important role in complications such as atherosclerosis, kidney disease, eye disease and neuropathies.
Oxidative stress leads to disease processes like inflammation. By understanding how oxidative stress and inflammation interact it’s hoped we can dampen down not just the oxidative stress but also the inflammation, which is now considered one of the driving factors in a number of these diseases. This is really where our work is heading because we now understand much more about this interaction.
How long has oxidative stress been a research focus for you?
In my post-doctoral years at Monash University, I developed a knockout mouse model that allowed me to look at conditions where oxidative stress could play an important role. In those days, I was particularly interested in looking at altering the antioxidant ratio because my doctoral studies investigated Down syndrome. Alterations in this antioxidant ratio were important in mediating some of the damage seen in Down syndrome individuals leading to premature ageing, so that’s really why we made the model. This was the knockout of the glutathione peroxidase-1 or GPx1 antioxidant gene – and it gave us a very useful tool to examine other diseases where oxidative stress is known to play a role. I was in the fortunate position then because we were the only group in Australia to have that knockout mouse.
When I joined the Baker Institute in 2004, I had the tools that let me look at diseases like atherosclerosis. The Baker had a focus on diabetic complications, which I was particularly interested in. After joining the Diabetic Complications Division, I began to investigate the consequences of increased oxidative stress in the diabetic milieu and focussed on atherosclerosis, and then expanded to other complications.
What are some of the milestones since then?
My group showed that if you knocked out the antioxidant enzyme GPx1 in diabetic mice it accelerates diabetes-associated atherosclerosis. That was in 2007. That really put us on the map as far as looking at that particular antioxidant and cardiovascular disease in the diabetic context.
Next, we administered a GPx1 mimetic, ebselen, to diabetic mice and found we were able to reduce atherosclerosis. This showed us that by bolstering a particular antioxidant enzyme we were able to reduce the burden of these diabetic complications. Work then developed around trying to understand the mechanism, looking in cell culture, where we manipulated the antioxidant defences, and we were able to show that by not having GPx1 it extends certain important pathways in the cell. One of the pathways is the MAP kinase pathway so by not having GPx1 it appears to extend the length of time this pro-inflammatory pathway is active, in a way pushing the pathway which then leads to inflammation. So we’ve now got a better understanding of the molecular pathways leading to inflammation.
In 2014, we published a paper showing that by bolstering global antioxidant defences, this was effective in reducing diabetes-associated atherosclerosis in diabetic mice. The drug that we used is being run in clinical trials by a pharmaceutical company in America with some exciting results in Phase II/III trials looking at pulmonary hypertension and also a disease called Alport syndrome.
What are your current research preoccupations?
One of the areas we’re focussing on is a transcription factor called Nrf2 which is the master regulator of oxidative stress. We’re looking at how this regulator interacts with inflammatory pathways. There are ways of upregulating this regulator and in doing so you can really push the protection against oxidative stress. We have certain compounds we’re particularly interested in looking at. Where we’re heading to with this work is trying to understand the relationship of Nrf2 and inflammation.
Indeed, the Baker Fellowship is all about trying to understand the interaction between these two pathways in the context of Diabetic complications such as vascular injury and cardiomyopathy. It allows me to focus on this area of interest for the next five years, building my team at the Baker and building my relationship with the new Diabetes Department at CCS. I feel that we will really come up with some novel ways to reduce these complications associated with diabetes. Our focus of course is going to be on the cardiovascular complications and that includes the vasculature, looking at things like endothelial dysfunction as well as looking at the diabetic heart together with the Ritchie lab here at the Baker. We’re also interested in looking at specific cell types involved in inflammation, such as the macrophages and how they’ll react to upregulation of Nrf2. Other cell types would be the cardiomyocytes, and how inflammation affects these cells. Projects include collaborations with investigators who are able to make human cardiomyocytes from pluripotent stem cells, a new area we’ll be going into as well.
Antioxidants entered the public imagination some years ago . . .
People hear about oxidative stress because they hear about antioxidants and dietary antioxidants. The thing to keep in mind is that at the clinical level antioxidants such as vitamins E and C have not proven efficacious despite a number of large clinical trials over the years, and unfortunately antioxidants have not proved effective against cardiovascular disease. We feel it’s better to develop a much more targeted antioxidant approach – by understanding the mechanisms we can develop far better strategies, for example bolstering Nrf2, which is one approach.
How has the field changed in the years since you entered it?
It’s been a gradual learning process over the years. Certainly there was a lot of interest initially but clinical trials into antioxidants were not as successful as first hoped. There was a lot of preclinical work done prior to these clinical trials which really did show that antioxidants were efficacious in reducing cardiovascular disease etc. but with the clinical trials not showing the expected outcomes, scientists were becoming a bit sceptical about the use of these antioxidants, particularly dietary antioxidants. But I think there’s a renewed push in the field, given greater knowledge and our better understanding of the need to have a targeted approach to antioxidant defences, so now we’re seeing work coming out with these better antioxidants. Also there are other groups focussing on targeting the mitochondria specifically in work that’s showing promise.
I think the other thing to remember with antioxidant defences is that you don’t want to be mopping up all your free radicals because they’re also important, and this is something that’s come out more recently – in signalling processes, so you do need to have a balance.
In other diseases, antioxidants have showed some efficacy, probably in relation to diseases of the brain like Alzheimer’s disease – I think there’s some evidence that, for example, vitamin E might be beneficial.