June 24, 2021
Researcher develops treatment to combat cardiovascular conditions caused by cells that line the walls of arteries
When you think about the cardiovascular system, what may immediately come to mind is the heart and large arteries, like the aorta, that are responsible for moving large volumes of blood throughout the body.
But the cardiovascular system is also made up of tiny blood vessels, about the size of a hair, that are not only responsible for carrying blood within tissues and organs of the body but are also critical in controlling blood pressure and regulating blood flow within these tissues.
It’s these resistance arteries, and in particular, the endothelium, the layer of cells that line the walls of the arteries, that are of interest to Libin Cardiovascular Institute researcher Dr. Andrew Braun, PhD.
“When the blood goes through the vasculature, the layer of cells it is in contact with is the endothelial layer, and it controls what the blood vessel does in terms of relaxing or contracting,” says Braun. “It may be a small proportion of the vessel wall, but it dictates how the artery functions.”
According to Braun, a common element in aging and in many cardiovascular conditions, including Type 2 diabetes which impacts about nine per cent of Canadians, is that the endothelial layer becomes impaired, a condition called endothelial dysfunction.
“Endothelial dysfunction is an early sign of potential coronary artery disease, stroke, and heart attack that starts really early on in the process,” says Braun, a professor in the Department of Physiology and Pharmacology at the Cumming School of Medicine (CSM). “If you could prevent or reverse endothelial dysfunction, it has been argued that you could either reduce or prevent the impact of cardiovascular diseases.”
Armed with this knowledge, Braun has taken a systematic approach to the problem of treating endothelial dysfunction by starting at the cellular level and working his way up.
Novel strategy, 'encouraging' results
He has developed a novel strategy to mitigate or reduce the severity of cardiovascular events in aging and Type 2 diabetic rats, whose condition means they have a two to four times greater risk of experiencing cardiovascular disease, such as atherosclerosis, coronary artery disease, high blood pressure and stroke.
A decade ago, Braun’s lab partnered with Dr. Heike Wulff, PhD, a professor of pharmacology at the University of California, Davis. Wulff, a medical chemist, created a molecule, SKA-31, that improves immune function by targeting key potassium ion channels within certain immune cells.
Knowing that these same potassium channels are also found in the endothelial layer, Braun’s lab began assessing the potential impact of the molecule on the cardiovascular system. Their findings are encouraging.
“What we found is that this molecule is beneficial in rodents who are aging or have Type 2 diabetes, whose endothelial function is naturally reduced,” says Braun. “We can make the endothelial function of an old animal look like that of a young animal.”
A study, recently published in Metabolism, revealed that the molecule also has the same effect in isolated blood vessels from people with Type 2 diabetes. Braun is cautiously optimistic that humans may respond to the molecule in a similar way as the animals.
In complementary work now being prepared for publication, Braun and coworkers have observed that feeding the molecule to rodents with Type 2 diabetes significantly improves their endothelial dysfunction and cardiac performance.
Braun’s research group found that the blood pressure in these animals decreased to a more normal range, reducing the animals’ risk of further cardiovascular complications, such as heart attacks and strokes.
Excitingly, the molecule seems to have no ill effects in animals that are aged or have Type 2 diabetes. It is also easy to administer — it can be taken orally.
Numerous steps before clinical trials
Although this therapy is yet to be tested in humans, Braun is encouraged by these pre-clinical observations.
“If we can validate that this strategy can mitigate the extent or severity of cardiovascular dysfunction in conditions like Type 2 diabetes, it would be a novel approach to treating patients, possibly to be used in conjunction with other therapeutics,” says Braun, noting there are numerous steps necessary before the possibility of clinical trials.
Dr. Todd Anderson, MD, a clinician-scientist and the vice-dean of the Cumming School of Medicine, says Braun’s work is exciting and highly translatable to many human diseases.
“Dysfunction of the endothelium of the microvasculature is responsible for a wide variety of human cardiovascular diseases,” says Anderson. “We are enthusiastic to see if the discoveries in his laboratory can have similar beneficial effects in humans.”
Andrew Braun is a professor in the department of Physiology and Pharmacology and a member of the CSM’s Libin Cardiovascular Institute. Braun’s work is funded in part by the Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council and the CSM’s Libin Cardiovascular Institute.
Todd Anderson is a professor in the department of Cardiac Sciences, vice-dean of the CSM and a member of the CSM’s Libin Cardiovascular Institute.