The cardiovascular system is made up of the heart and large arteries, like the aorta, and is responsible for moving large volumes of blood around the body. But it’s also composed of tiny blood vessels, about the size of a hair, that transport blood within the tissues and organs of the body.
The layer of cells lining both large and small blood vessels, called the vascular endothelium, is critical in regulating blood pressure and blood flow throughout the body. Dysfunction of this cell lining (endothelial dysfunction) directly contributes to the development of cardiovascular disease and is an early sign of coronary artery disease, stroke, and heart attack.
Preventing or reversing endothelial dysfunction has the potential to reduce or reverse cardiovascular diseases and finding a treatment is urgent for the nine per cent of Canadians with Type 2 diabetes, who are two to four times more likely to develop cardiovascular disease.
Dr. Andy Braun, PhD, a professor in the Department of Physiology and Pharmacology at the Cumming School of Medicine, has been systematically working on this problem — with a team of international collaborators — for the past decade.
“Our work has revealed a way to restore function in the arteries of animal models with Type 2 diabetes,” says Braun. “We have developed a drug therapy that targets specific proteins in the endothelium and have seen long-term improvement in cardiovascular health in rats with Type 2 Diabetes.”
Braun recently received a $1-million, five-year Canadian Institutes of Health Research (CIHR) grant to continue this work.
Protein improves endothelial function
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, was developing novel chemical compounds to regulate inflammatory responses 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 these small molecules on the cardiovascular system. Their findings are encouraging.
“We found that one of these small molecules, SKA-31, is beneficial in rodents who are aging or have Type 2 diabetes, animals 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.”
Researchers fed the molecule to rodents with Type 2 diabetes and saw significant improvements in their endothelial dysfunction and cardiac performance. 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 the animals.
Although SKA-13 has yet to be administered to humans, outside of observing the molecule’s effect on isolated blood vessels of people with Type 2 diabetes, Braun is encouraged by the pre-clinical observations.
Moving forward
The recent grant will allow Braun and his team to take an even more robust look at the impact of the novel therapy.
The team will dig deeper into the molecular and cellular mechanisms behind how blood pressure and flow are regulated by the endothelial cells and how the novel therapy is impacting these processes. They will also examine potential sex differences, side effects, drug interactions, and how prolonged use of the novel therapy impacts the health of the cardiovascular system.
“This new funding allows us to establish more foundational knowledge, so we have the confidence to move closer to clinical trials,” says Braun. “If we can validate that this strategy can mitigate the extent or severity of cardiovascular dysfunction in conditions like Type 2 diabetes, it will be a novel approach to treating patients.”
The treatment may also be beneficial for other cardiovascular conditions, like atherosclerosis, which is a thickening or hardening of the arteries caused by a buildup of plaque that can lead to a heart attack or stroke.
“This may have an impact on other conditions, and that is one of the things that excites me about this research,” says Braun. “Our overall goal is to improve outcomes for patients.”
Dr. Todd Anderson, MD'85, a clinician-scientist and the dean of the CSM, 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.”
