Inhibition of MMP 2 protects the endothelial glycocalyx and improves diastolic function in diabetic cardiomyopathy

Buffonge, S.; Qiu, Y.; Fawaz, S.; Gamez, M.; Crompton, M.; Butler, M. J.; Welsh, G. I.; Madeddu, P.; Foster, R. R.; Satchell, S. C.

doi:10.1101/2023.12.18.572183

bioRxiv · 10.1101/2023.12.18.572183

Inhibition of MMP 2 protects the endothelial glycocalyx and improves diastolic function in diabetic cardiomyopathy

Buffonge, S.·Qiu, Y.·Fawaz, S.·Gamez, M.·Crompton, M.·Butler, M. J.·Welsh, G. I.·Madeddu, P.·Foster, R. R.·Satchell, S. C.

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Abstract

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 (SDC4), and are upregulated in diabetes. We tested the hypothesis that inhibition of MMP2/9 can protect the EGlx and improve diastolic function in diabetic cardiomyopathy. 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 TNF- and SB-3CT. 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- caused an increase in MMP9 activity and SDC4 shedding from human coronary microvascular endothelial cells. Treatment with SB-3CT reduced MMP9 activity and prevented SDC4 shedding. Knockdown of MMP9 expression prevented TNF- induced SDC4 shedding. This study demonstrates MMP2/9 inhibition as a strategy to protect the EGlx and improve diastolic function in diabetic cardiomyopathy. Our findings suggest new avenues for therapeutic interventions in cardiovascular complications associated with diabetes. Statements and DeclarationsO_ST_ABSCompeting interestsC_ST_ABSThe authors have no competing interests to declare that are relevant to the content of this article.

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Buffonge, S., Qiu, Y., Fawaz, S., Gamez, M., Crompton, M., Butler, M. J., Welsh, G. I., Madeddu, P., Foster, R. R., Satchell, S. C.. 2023-12-18. Inhibition of MMP 2 protects the endothelial glycocalyx and improves diastolic function in diabetic cardiomyopathy. https://doi.org/10.1101/2023.12.18.572183

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