Endothelial Glycocalyx and Cardiomyocyte Damage Is Prevented by Recombinant Syndecan-1 in Acute Myocardial Infarction.

The outer layer of endothelial cells (ECs), consisting of the endothelial glycocalyx (eGC) and the cortex (CTX), provides a protective barrier against vascular diseases. Structural and functional impairments of their mechanical properties are recognized as hallmarks of endothelial dysfunction and can lead to cardiovascular events, such as acute myocardial infarction (AMI). This study investigated the effects of AMI on endothelial nanomechanics and function and the use of exogenous recombinant syndecan-1 (rSyn-1), a major component of the eGC, as recovering agent. ECs were exposed in vitro to serum samples collected from patients with AMI. In addition, in situ ECs of ex vivo aorta preparations derived from a mouse model for AMI were employed. Effects were quantified by using atomic force microscopy-based nanoindentation measurements, fluorescence staining, and histologic examination of the mouse hearts. AMI serum samples damaged eGC/CTX and augmented monocyte adhesion to the endothelial surface. In particular, the anaphylatoxins C3a and C5a played an important role in these processes. The impairment of endothelial function could be prevented by rSyn-1 treatment. In the mouse model of myocardial infarction, pretreatment with rSyn-1 alleviated eGC/CTX deterioration and reduced cardiomyocyte damage in histologic analyses. However, echocardiographic measurements did not indicate a functional benefit. These results provide new insights into the underlying mechanisms of AMI-induced endothelial dysfunction and perspectives for future studies on the benefit of rSyn-1 in post-AMI treatment.

Dysregulated complement activation during acute myocardial infarction leads to endothelial glycocalyx degradation and endothelial dysfunction via the C5a:C5a-Receptor1 axis.

Introduction: Complement-mediated damage to the myocardium during acute myocardial infarction (AMI), particularly the late components of the terminal pathway (C5-convertase and C5b-9), have previously been characterized. Unfortunately, only few studies have reported a direct association between dysregulated complement activation and endothelial function. Hence, little attention has been paid to the role of the anaphylatoxin C5a. The endothelial glycocalyx (eGC) together with the cellular actin cortex provide a vasoprotective barrier against chronic vascular inflammation. Changes in their nanomechanical properties (stiffness and height) are recognized as hallmarks of endothelial dysfunction as they correlate with the bioavailability of vasoactive substances, such as nitric oxide (NO). Here, we determined how the C5a:C5aR1 axis affects the eGC and endothelial function in AMI. Methods: Samples of fifty-five patients with ST-elevation myocardial infarction (STEMI) vs. healthy controls were analyzed in this study. eGC components and C5a levels were determined via ELISA; NO levels were quantified chemiluminescence-based. Endothelial cells were stimulated with C5a or patient sera (with/without C5a-receptor1 antagonist "PMX53") and the nanomechanical properties of eGC quantified using the atomic force microscopy (AFM)-based nanoindentation technique. To measure actin cytoskeletal tension regulator activation (RhoA and Rac1) G-LISA assays were applied. Vascular inflammation was examined by quantifying monocyte-endothelium interaction via AFM-based single-cell-force spectroscopy. Results: Serum concentrations of eGC components and C5a were significantly increased during STEMI. Serum and solely C5a stimulation decreased eGC height and stiffness, indicating shedding of the eGC. C5a enhanced RhoA activation, resulting in increased cortical stiffness with subsequent reduction in NO concentrations. Monocyte adhesion to the endothelium was enhanced after both C5a and stimulation with STEMI serum. eGC degradation- and RhoA-induced cortical stiffening with subsequent endothelial dysfunction were attenuated after administering PMX53. Conclusion: This study demonstrates that dysregulated C5a activation during AMI results in eGC damage with subsequent endothelial dysfunction and reduced NO bioavailability, indicating progressively developing vascular inflammation. This could be prevented by antagonizing C5aR1, highlighting the role of the C5a:C5a-Receptor1 axis in vascular inflammation development and endothelial dysfunction in AMI, offering new therapeutic approaches for future investigations.

Prolonged Door-to-Balloon Time Leads to Endothelial Glycocalyx Damage and Endothelial Dysfunction in Patients with ST-Elevation Myocardial Infarction.

Damage to the endothelial glycocalyx (eGC) has been reported during acute ischemic events like ST-elevation myocardial infarction (STEMI). In STEMI, a door-to-balloon time (D2B) of <60 min was shown to reduce mortality and nonfatal complications. Here, we hypothesize that eGC condition is associated with D2B duration and endothelial function during STEMI. One hundred and twenty-six individuals were analyzed in this study (STEMI patients vs. age-/sex-matched healthy volunteers). After stimulating endothelial cells with patient/control sera, the eGC's nanomechanical properties (i.e., height/stiffness) were analyzed using the atomic force microscopy-based nanoindentation technique. eGC components were determined via ELISA, and measurements of nitric oxide levels (NO) were based on chemiluminescence. eGC height/stiffness (both p < 0.001), as well as NO concentration (p < 0.001), were reduced during STEMI. Notably, the D2B had a strong impact on the endothelial condition: a D2B > 60 min led to significantly higher serum concentrations of eGC components (syndecan-1: p < 0.001/heparan sulfate: p < 0.001/hyaluronic acid: p < 0.0001). A D2B > 60 min led to the pronounced loss of eGC height/stiffness (both, p < 0.001) with reduced NO concentrations (p < 0.01), activated the complement system (p < 0.001), and prolonged the hospital stay (p < 0.01). An increased D2B led to severe eGC shedding, with endothelial dysfunction in a temporal context. eGC components and pro-inflammatory mediators correlated with a prolonged D2B, indicating a time-dependent immune reaction during STEMI, with a decreased NO concentration. Thus, D2B is a crucial factor for eGC damage during STEMI. Clinical evaluation of the eGC condition might serve as an important predictor for the endothelial function of STEMI patients in the future.