Endothelial glycocalyx is damaged in diabetic cardiomyopathy: angiopoietin 1 restores glycocalyx and improves diastolic function in mice

Abstract

Aims/hypothesis Diabetic cardiomyopathy (DCM) is a serious and under-recognised complication of diabetes. The first sign is diastolic dysfunction, which progresses to heart failure. The pathophysiology of DCM is incompletely understood but microcirculatory changes are important. Endothelial glycocalyx (eGlx) plays multiple vital roles in the microcirculation, including in the regulation of vascular permeability, and is compromised in diabetes but has not previously been studied in the coronary microcirculation in diabetes. We hypothesised that eGlx damage in the coronary microcirculation contributes to increased microvascular permeability and hence to cardiac dysfunction. Methods We investigated eGlx damage and cardiomyopathy in mouse models of type 1 (streptozotocin-induced) and type 2 (db/db) diabetes. Cardiac dysfunction was determined by echocardiography. We obtained eGlx depth and coverage by transmission electron microscopy (TEM) on mouse hearts perfusion-fixed with glutaraldehyde and Alcian Blue. Perivascular oedema was assessed from TEM images by measuring the perivascular space area. Lectin-based fluorescence was developed to study eGlx in paraformaldehyde-fixed mouse and human tissues. The eGlx of human conditionally immortalised coronary microvascular endothelial cells (CMVECs) in culture was removed with eGlx-degrading enzymes before measurement of protein passage across the cell monolayer. The mechanism of eGlx damage in the diabetic heart was investigated by quantitative reverse transcription-PCR array and matrix metalloproteinase (MMP) activity assay. To directly demonstrate that eGlx damage disturbs cardiac function, isolated rat hearts were treated with enzymes in a Langendorff preparation. Angiopoietin 1 (Ang1) is known to restore eGlx and so was used to investigate whether eGlx restoration reverses diastolic dysfunction in mice with type 1 diabetes. Results In a mouse model of type 1 diabetes, diastolic dysfunction (confirmed by echocardiography) was associated with loss of eGlx from CMVECs and the development of perivascular oedema, suggesting increased microvascular permeability. We confirmed in vitro that eGlx removal increases CMVEC monolayer permeability. We identified increased MMP activity as a potential mechanism of eGlx damage and we observed loss of syndecan 4 consistent with MMP activity. In a mouse model of type 2 diabetes we found a similar loss of eGlx preceding the development of diastolic dysfunction. We used isolated rat hearts to demonstrate that eGlx damage (induced by enzymes) is sufficient to disturb cardiac function. Ang1 restored eGlx and this was associated with reduced perivascular oedema and amelioration of the diastolic dysfunction seen in mice with type 1 diabetes. Conclusions/interpretation The association of CMVEC glycocalyx damage with diastolic dysfunction in two diabetes models suggests that it may play a pathophysiological role and the enzyme studies confirm that eGlx damage is sufficient to impair cardiac function. Ang1 rapidly restores the CMVEC glycocalyx and improves diastolic function. Our work identifies CMVEC glycocalyx damage as a potential contributor to the development of DCM and therefore as a therapeutic target. Graphical abstract

Effects of Sodium-Glucose Cotransporter-2 Inhibitors on Urine Albumin to Creatinine Ratio in Type 2 Diabetes Mellitus Patients and Medication Care

“…In the world, the number of DM patients had quadrupled in the past three decades, and meanwhile, DM was the ninth major cause of death, among which Asia had become the major area of the rapidly emerging T2DM global epidemic, and most T2DM patients always had at least one complication [ 23 ]. The complexity of T2DM treatment and care were very challenging because they involved the prevention of organ damage and complications [ 23 ], including chronic damage and dysfunction of various tissues, especially kidneys [ 4 ], blood vessels [ 5 ], nerves [ 6 ], and heart [ 7 ], among which kidney damage was one of the most common microvascular complications in DM patients, which brought great challenges to the treatment and nursing for DM patients.…”

“…In the world, the number of DM patients had quadrupled in the past three decades, and meanwhile, DM was the ninth major cause of death, among which Asia had become the major area of the rapidly emerging T2DM global epidemic, and most T2DM patients always had at least one complication [23]. The complexity of T2DM treatment and care were very challenging because they involved the prevention of organ damage and complications [23], including chronic damage and dysfunction of various tissues, especially kidneys [4], blood vessels [5], nerves [6], and heart [7], among SGLT-2 inhibitors were a group of antidiabetic drugs, which had the ability to reduce the blood sugar via inhibiting SGLT-2 [24]. Furthermore, except for lowering blood sugar [25][26][27][28][29][30], SGLT-2 inhibitors also had abilities to lose weight [24,31,32], reduce cardiovascular outcomes and mortality risk [33], and play renal protective effect [15].…”

“…Formulas (4)- (7) showed variabilities of interstudy which were described by exponential or additive error models:…”

“…What was more important was that DM could be complicated with multiple diseases significantly increasing the death risk of DM patient [ 1 ]. As everyone knows, long-term hyperglycemia would result in chronic damage and dysfunction of various tissues, especially kidneys [ 4 ], blood vessels [ 5 ], nerves [ 6 ], and heart [ 7 ], among which kidney damage was one of the most common microvascular complications in DM patients, which brought great challenges to the treatment and nursing for DM patients.…”

Vascular Endothelial Glycocalyx Damage and Potential Targeted Therapy in COVID-19

“…Up to now, there are relatively few studies on the mechanism by which MMPs influence glycocalyx degradation. In a mouse model of type 1 diabetes, increased MMP activity was identified as a potential mechanism of endothelial glycocalyx damage, with loss of syndecan-4 [ 122 ]. In a mouse model of COVID-19, the administration of the ADAM17/MMP inhibitors significantly improved lung histology and prevented leukocyte infiltration and endothelial activation [ 123 ], suggesting its beneficial role in improving the endothelial function, although whether ADAM17/MMP inhibitors directly affect glycocalyx needs further investigation.…”