The link between diabetes and heart disease

The link between diabetes and heart disease

It is Friday afternoon and John Pernow’s group gather in the fish tank on floor 2. Champagne bottles and cake are on the table but these are not ordinary ingredients for a lab meeting stretching over to the weekend, but instead to celebrate PhD student Oskar Kövamee’s recent engagement. What does seem to be normal is the high spirits of everyone and the jokes and laughter are frequent throughout the two-hour meeting. Most members are presenting their current data and the discussions orbit around how to ensure accumulation of data; the animals used for the studies are affected by the daily blasting in the local construction area and new patients and healthy individuals need to be recruited. The group discussing their study requirements is reminiscent of a synchronized orchestra gently conducted by John Pernow. “The group consists of researchers with different backgrounds and competence which creates a very stimulating atmosphere to work in. It is an excellent mixture of clinicians, biologists and pharmacologists” John says.

The Pernow group works with cardiology and their research focus is on endothelial cell biology and vascular reactivity as well as how to protect from injuries caused by myocardial ischemia-reperfusion. The researchers have recently focused their attention on the association between type 2 diabetes (T2D) and cardiovascular disease. Levels of factors regulating vascular reactivity, such as the arginase enzyme (constriction and dilatation of the blood vessels) derived from endothelial cells have been discovered to be upregulated in patients with cardiovascular disease, as well as in diabetes. It is now well recognized that T2D is a major risk factor for developing atherosclerosis and ischemic heart disease. The Pernow group and others have established that arginase activity in vessels is upregulated in diabetes and functional studies in both animal models and patients indicate that the response of arginase blockade is more articulated in diabetic subjects compared to in healthy controls. These interesting effects have been shown not only to originate from the endothelial cells in the vessels but even more so from red blood cells in the circulation. The translational approach of the Pernow group is evident and bridges the molecular arginase experiments in the lab to clinical trials of arginase blockers in patients. 

Ali Mahdi has been recently registered as a PhD student in John Pernow’s group. He is a medical student eight semesters into the medical programme. He has been a part of the research group for two years and this semester he will do full time research. Ali’s research project concerns digging deeper into the question about diabetes, red blood cells and vascular impairment. He will work with both clinical research investigating arginase blockers in obese patients in collaboration with Ersta hospital, and also with experimental models in the lab. The group has previously established using a model of an isolated heart that it is in fact the arginase located in the red blood cells that controls the negative consequences of ischemia-reperfusion and also that this is where the arginase blockade has its effect. When questioned what he enjoys most in research Ali says ”There is a charm in testing hypotheses in the lab. The group has well established model systems so it’s always quick and easy to test a new approach”. Ali is just in the beginning of his doctoral training and there is no doubt about his enthusiasm for research. But what specialty within medicine does he see himself practicing in the future? After some thought he says “perhaps anesthesiology, I like that there is so much human physiology involved”.

Arginase effect on vascular function

In a healthy vessel there is a balance between tension and relaxation in the vessel wall that regulates blood flow. The balance is maintained on the one hand by arginase activity resulting in the formation of reactive oxygen species (ROS), and vasoconstriction and on the other hand through the formation of nitric oxide (NO) and vasodilatation. Both processes rely on the amino acid L-arginine as a substrate and endothelial NO synthase (eNOS) that mediates the pathway leading to NO formation competes with the arginase enzyme.  In several diseases the activity of arginase is increased which leads to additionally impaired NO production and an escalation of ROS production, thereby driving the cycle towards increased vasoconstriction, vessel wall thickening and arterial stiffness so that the balance is lost.