May 29, 2017
New $6.7 million NIH grant seeks to explain role of key transcription factors in age-related cardiovascular disease
Harrington Heart & Vascular Institute Innovations - Spring 2017
Kruppel-like factors (KLFs) are a seemingly endless source of inquiry for Mukesh K. Jain, MD, Chief Scientific Officer, University Hospitals and UH Harrington Heart & Vascular Institute; Professor of Medicine, Case Western Reserve University School of Medicine. For the past 15 years, he and his team have explored this family of 18 genetic factors, elucidating their essential roles in immune, metabolic and cardiovascular function. With regard to cardiovascular health, they’ve shown that KLFs are required to maintain optimal function of the heart and blood vessels in health and that loss of KLFs leads to cardiovascular dysfunction. Importantly, they’ve shown that KLF levels are reduced in patients with cardiovascular disease, suggesting that approaches to augment their levels could be leveraged for therapeutic gain.
“Our published and unpublished work over the past dozen years, focused mainly on three members of this gene family, namely KLF2 and KLF4 and KLF15, has led to the appreciation that these factors are essential regulators of all cardinal functions of blood vessels, including vasoreactivity and maintenance of an anti-thrombotic, anti-adhesive state,” says Dr. Jain, who is Chief Scientific Officer at University Hospitals and UH Harrington Heart & Vascular Institute. “For example, deletion of KLF4 in endothelium leads to altered vascular reactivity, vascular stiffness and atherothrombosis, while sustained expression of KLF4 confers anti-parallel effects. Further, loss of KLF15, which is expressed in both cardiac and smooth muscle cells, leads to heart failure and aortic aneurysm formation.“
Dr. Jain has received grant support for this work from the National Heart, Lung & Blood Institute for the past dozen years. Now, he has received NIH’s largest individual award -- $6.7 million over seven years – to take this research to the next level. He and his team will be looking to determine whether KLFs govern aging across multicellular life, through the lens of the cardiovascular system.
“The appreciation that KLFs regulate age-associated diseases in the cardiovascular system led us to hypothesize that KLFs may regulate lifespan, healthspan, or both,” he says.
Preliminary studies in C. elegans worms provide some support for this idea. Results show that worms with depleted KLFs live a 20 to 30 percent shorter life, while those with sustained KLFs live 30 percent longer. At the same time, worms with sustained KLFs also are more vibrant.
“We showed that worms that had high levels of KLFs behave like younger worms, as evidenced by increased motility, fertility and better brain health,” Dr. Jain says. “We’re not just interested in lifespan. We’re also interested in healthspan – how healthy you are while you’re living. The fact that these animals are more healthy as they age is of great interest.”
Using these results as a foundation, Dr. Jain and his team are determining whether they hold true in mammals, with a special focus on age-related cardiovascular disease such as cardiac hypertrophy and failure or vascular stiffness and hypertension. So far, the results are encouraging.
“We now have good evidence in mice that if you deplete KLFs in their blood vessel or heart as they age, they start to develop heart failure earlier in life and have stiffer blood vessels,” Dr. Jain says. “If you enhance KLF in the blood vessel, the blood vessels are more pliable. That’s an early indicator that maybe we’re on to something that’s conserved from a worm to a mammal. That conservation across metazoan life suggests that KLFs are probably pretty important.”
Although final results of this research are still years away, Dr. Jain and his team are working with UH’s Harrington Discovery Institute to develop plans for applying their discoveries.
“The Harrington Discovery Institute was founded to help take these early discoveries and try to see if you could make a meaningful therapeutic impact,” he says. “We are trying to find molecules – maybe from existing drugs or maybe new molecules – that will maintain KLF levels in animals as they age. If you could do that, you may have the ability to extend life, but even more importantly, extend healthy life.”
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