Identifying matrix metalloproteinases as a therapeutic target to protect the coronary microvascular endothelial glycocalyx in diabetic cardiomyopathy

Abstract

Introduction:
The coronary microvascular endothelial glycocalyx (EGlx) is a vital regulator of vascular permeability and EGlx damage contributes to the development of diabetic cardiomyopathy. Matrix metalloproteinases 2 and 9 (MMP2/9) have been identified as key enzymes in the degradation of EGlx components, notably syndecan 4, and are upregulated in diabetes. This thesis aimed to investigate if inhibition of MMP2/9 can protect the coronary microvascular EGlx, and improve diastolic function in diabetic cardiomyopathy.

Methods:
Type 1 diabetes was induced in FVB mice by streptozotocin (STZ) injections. Mice were treated with daily injections of the MMP2/9 inhibitor, SB-3CT, for 2 weeks from 7 weeks post STZ. Echocardiography was utilised to assess heart function and lectin staining for the measurement of EGlx depth. Immunolabelling of heart sections for albumin provided an indication of albumin extravasation. A mechanism of EGlx shedding was investigated in vitro in human coronary microvascular endothelial cells treated with tumour necrosis factor α and SB-3CT.

Results:
Diabetic mice developed diastolic dysfunction from 6 weeks post STZ. MMP2/9 inhibition reversed diastolic dysfunction, EGlx thinning and albumin extravasation in diabetic animals. In vitro, TNF-α caused an increase in MMP9 activity and syndecan 4 shedding from human coronary microvascular endothelial cells. Treatment with SB-3CT reduced syndecan 4 shedding.

Conclusion:
This thesis has identified MMPs as a therapeutic target to protect the coronary microvascular EGlx and improve diastolic function in diabetic cardiomyopathy.

Date of Award	5 Dec 2023
Original language	English
Awarding Institution	University of Bristol
Supervisor	R R Foster (Supervisor), Paolo R Madeddu (Supervisor) & Simon C Satchell (Supervisor)