At a talk held at the University of Leeds on the 1st February 2017, Dr. Richard Pease, the principal research fellow for the University of Leeds’ Division of Cardiovascular and Diabetes research, concluded further research still needs to be carried out into whether specific transglutaminases enzymes can influence cardiovascular repair.
The benefits of this research include finding a treatment for thrombosis (blood clots), furthering new drug discovery and seeing if it can play a role in strengthening and repairing arteries and the myocardium (the muscular tissue of the heart).
Thrombosis occurs inside a blood vessel, obstructing the flow of blood through the circulatory system. They can occur in veins or arteries and can be caused by a range of factors, such as strokes, heart failure, and obesity.
Dr. Pease has collaborated with other researchers, such as Dr. Chris Jackson from the Bristol Heart Institute and their research has concentrated solely on the reactions of two types of transglutaminases: (1) TG2; and (2) FXIII-A. Their trials focused on the role these enzymes played in clot stabilisation. Specialised genetically modified mice were bred, used and fed fat to test the effects of the transglutaminases enzymes.
It has been suggested by other scholars that TG2 and FXIII-A act redundantly in various functions, such as repair processes and stabilisation of blood clots, so Dr. Pease bred mice with two genes knocked out of their DNA structure (known as KO Mice) and mice with three genes knocked out (also known as TKO Mice) to test if these assumptions were true.
“For the TG2,” stated Pease, “Despite hundreds of functions being thought of before the KO mouse was made, the surprise what that it was asymptomatic.” Additionally, with the Human TG2, it was found that complete deficiency had not been described, which meant it was lethal or asymptomatic under normal conditions.
For the FXIII-A enzyme, it was found that there was a prolongation of bleeding time for the KO mice. Male KO mice were prone to thoracic bleeding (from the neck and the abdomen) and female KO mice would hemorrhage in late pregnancy.
“Two strange things occurred in this study,” explained Pease. “Unexpectedly, there were a lot of mouse deaths among the fat fed FXIII-A mice – both the KO and TKO. FXIII-A KO mice had a high spontaneous death rate of 17% due to thoracic hemorrhage, and there was a massive amount of cardiac fibrosis found in the FXIII-A TKO mice.” Large thoracic vessels were rupturing in the fat-fed FXIII-A mice and small myocardial vessels appeared to be leaking in the TKO mice.
A difficulty found in the study is that mice are lacking specific genes that humans have, and this specific gene may protect the pathways of the TG2. The steps that caused extracellular TG2 to be activated is still unknown.
Dr. Pease is hoping to look further into this cell-mediated transfer and see if these transglutaminases are active within the transferred cell. The relevant transgenic mice and viruses will be provided by the Pasteur Institute, who are happy to collaborate on this study.
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