12 Dec 2018

Funding drives new directions in oxidative stress research for diabetes and heart disease

Professor Karin Jandeleit-Dahm
has won two NHMRC project grants
Series about National Health and Medical Research Council (NHMRC) Project Grant recipients in Central Clinical School (CCS) starting in 2019

Professor Karin Jandeleit-Dahm was awarded two project grants for research on:
  • Targeting Nox5 to prevent atherosclerosis and aneurysm formation
  • Lipoxins protect against diabetes associated atherosclerosis.
by Anne Crawford

In 2017 Central Clinical School’s Professor Karin Jandeleit-Dahm and her team in the Department of Diabetes exposed a protein that potentially plays an important role in promoting diabetic kidney disease with a view to inhibiting it in a treatment.

Now Professor Jandeleit-Dahm has been funded by the NHMRC to explore the effect of Nox5, a pro-oxidant enzyme, in cardiovascular disease.

This body of work looks at oxidative stress, a process caused by the overproduction of reactive oxygen species that damages and ultimately kills many cell types and which is implicated in a number of diseases.

“We have compelling evidence in preliminary data that the Nox5 pathway is active in the vasculature and will lead to vascular injury, atherosclerosis (hardening of the arteries) and even aneurysms,” Prof. Jandeleit-Dahm said.

Prof. Jandeleit-Dahm, who heads the Diabetes and Kidney Disease Laboratory, is working on the project with Chief Investigator B, long-term collaborator and renowned hypertension expert Professor Rhian Touyz from the BHF Glasgow Cardiovascular Research Centre, University of Glasgow.

“I’m extremely happy that we have been successful at receiving this funding. For my group it is very important – we were very much depending on it to continue this work,” Prof. Jandeleit-Dahm said. “Now we can really look into the future.”

The researchers will use unique Nox5 transgenic mice and rabbit models as well as a novel Nox5 rabbit in which the Nox5 gene has been ‘knocked out’, to examine its function. They will also conduct in vitro studies in vascular cells to either excise or overexpress Nox5 to examine the mechanisms involved.

“We want to develop a specific inhibitor of these Nox5 pathways to prevent vascular disease,” Prof. Jandeleit-Dahm said. “I’m a clinician-scientist so the ultimate aim is to reduce the burden of this disease in the population.

“Even with statins, aspirin and other treatments we still have a major gap – people still get heart disease and strokes particularly in diabetes,” she said.

Cardiovascular disease is the leading cause of death and disease in Australia, and the most common cause of morbidity and mortality in diabetes.

The researchers are comparing Nox5 inhibition with existing treatments including the commonly used Angiotensin-converting enzyme (ACE) inhibitors.

The grant will also investigate a novel mitochondrial oxidative stress inhibitor which interacts with Nox5.

“We have evidence that Nox5 activation is also associated with mitochondrial damage in vasculature. This could be a completely new target to address atherosclerosis and heart disease as well as being important to diabetes.

“It’s looking at a different aspects of oxidative stress formation in the vasculature and we are looking at therapeutic targets which complement each other. We are positive that we will get a conclusive answer out of the project which will be clinically relevant,” Prof. Jandeleit-Dahm said.

Small molecule may make big gains in fighting heart disease

Heart disease is the leading cause of death in people with diabetes, accounting for
more than 70% of mortality in this group. Novel approaches to more effectively tackle diabetes-associated atherosclerosis (DAA) – the narrowing of the arteries that leads to heart disease – are badly needed.

Monash Department of Diabetes researchers have been funded more than $936,000 over four years to investigate a promising strategy to combat heart disease including in diabetes.

The researchers, Chief Investigators Professor Karin Jandeleit-Dahm (CIA) and Dr Phillip Kantharidis (CIB), will test the protective effect of a family of molecules, including Lipoxin A4, a naturally occurring small molecule, against the development and progression of atherosclerosis.

“Lipoxin A4 is a member of the resolvin family of molecules, which are known to be deficient in patients with diabetes,” Dr Kantharidis said. “These molecules are produced by our bodies as a way of promoting the resolution of inflammation, and especially against the pathological processes that are known to drive the development of atherosclerosis,” he said.

The scientists will compare an approach using an analogue of Lipoxin A4 (CT4-43) – alone or in combination with other treatments – to current standard treatments called angiotensin receptor blockers (blood pressure lowering medications). They will also compare it with new treatments now in development for macrovascular complications, such as Nox and NLRP3 inflammasome inhibitors.

“Our studies have provided a strong proof of concept, demonstrating that Lipoxin A4 confers anti-proliferative and vasoprotective effects in diabetes,” Dr Kantharidis said.

“The use of Lipoxins provides us with a novel treatment strategy based on the simultaneous resolution of inflammation, angiogenesis and proliferation, all pathogenic processes involved in atherosclerosis,” he said.

Dr Kantharidis said the approach has the potential to change the way cardiovascular disease is managed in the context of diabetes.

“Positive findings to date provide the impetus to consider clinical trials with what appears to be a very safe class of drugs,” he said.

The Monash scientists are collaborating with Professor Catherine Godson (CIC), an expert in Lipoxin biology who works at University College, Dublin. The collaborators bring together preclinical expertise, animal models of diabetic complications, and unique reagents, including the Lipoxin analogues.

“Our team is in a very strong internationally competitive and unique position to determine the therapeutic potential of Lipoxins as a novel approach for the treatment of major diabetic complications,” Prof. Jandeleit-Dahm said.

“Ultimately, we aim to translate our preclinical findings to the clinic and to develop and effective and safe treatment to reduce the burden of cardiovascular disease in diabetes and beyond.”

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