AbstractThe role of leucine rich alpha-2-glycoprotein-1 (LRG1) as a biomarker has been demonstrated in various cancers, acute myeloid leukaemia, ulcerative colitis and others, where its functions have been studied in aberrant neovascularisation in the eye as well as being a key player in epithelial-mesenchymal transition (EMT). Its involvement in angiogenesis and inflammation have recently been established, making it a potential candidate as a therapeutic target for many diseases.
We hypothesised based on the known pathophysiology of preeclampsia (PE) involving dysfunctional angiogenesis and inflammation, that LRG1 levels may be altered in women who develop PE during pregnancy, with particular interest in women with diabetes. We found that LRG1 plasma concentration is increased in women who developed PE, and this occurred specifically in diabetic women. In vitro studies revealed that the expression of LRG1 from trophoblast cells is reduced in hypoxia and this reduction is exacerbated in hyperglycaemic conditions. This is coupled with a reduction of PPARβ/δ, although PPARβ/δ does not seem to act downstream of LRG1 in trophoblasts. The mechanism of LRG1 reduction was found not to be mediated by miR-17. In vivo mouse models showed that LRG1 was reduced in diabetic Akita (Ins2Akita/Ins2+) mouse placenta compared to non-diabetic controls. This was accompanied with a net reduction in mesenchymal markers indicating a less invasive nature in the placenta.
Due to the relationship of PE and the development of future cardiovascular disease. We studied the connection between LRG1 and heart failure. Left ventricular septal tissue from patients who died from end stage heart failure revealed a downregulation of LRG1 expression in patients with ischaemic cardiomyopathy, dilated cardiomyopathy and hypertrophic cardiomyopathy compared to patients who died from non-cardiac issues. No significant difference was found between control and patients with left ventricular hypertrophy. We then studied the functional association of LRG1 with the migration of human cardiac fibroblast cells and found that recombinant LRG1 increased the migration of cells whereas LRG1 knockdown reduced cell migration. This process may be mediated by PPARβ/δ. Our studies led us to investigate LRG1 (and sST2 and IL6) as a biomarker in patients with heart failure to differentiate between heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF) or non-heart failure patients. Use of two cohorts of patients from Sub-Saharan Africa and two of European Caucasian showed that LRG1, sST2 and IL-6 did not predict the development of heart failure in general and would be a poor marker for diagnosis.
|Date of Award||Jul 2020|
|Supervisor||Chris Watson (Supervisor)|