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.

Proinflammatory cytokines target vascular endothelial cells during COVID-19 infections. In particular, the endothelial glycocalyx (eGC), a proteoglycan-rich layer on top of endothelial cells, was identified as a vulnerable, vasoprotective structure during infections. Thus, eGC damage can be seen as a hallmark in the development of endothelial dysfunction and inflammatory processes. Using sera derived from patients suffering from COVID-19, we could demonstrate that the eGC became progressively worse in relation to disease severity (mild vs severe course) and in correlation to IL-6 levels. This could be prevented by administering low doses of spironolactone, a well-known and highly specific aldosterone receptor antagonist. Our results confirm that SARS-CoV-2 infections cause eGC damage and endothelial dysfunction and we outline the underlying mechanisms and suggest potential therapeutic options.

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.

Background: Complement-mediated myocardial and vascular injury is a hallmark of ST-elevation myocardial infarction (STEMI). Dysregulated activation of complement component C5 has been implicated in endothelial dysfunction, exacerbated inflammatory responses, and progressive vascular damage during acute ischemia. Experimental data suggest that antagonizing the C5a–C5aR1 axis may attenuate these effects, but clinical evidence regarding the impact of established C5 inhibitors during STEMI remains limited. Methods: To investigate real-world cardiovascular and thromboembolic outcomes associated with C5 inhibition during STEMI, a propensity score-matched retrospective cohort study using the TriNetX Global Collaborative Network was performed. 174 patients with STEMI who had received Eculizumab or Ravulizumab for pre-existing complement-mediated disorders (paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, neuromyelitis optica, or myasthenia gravis) prior to the index event were compared with 174 matched patients without C5-inhibitor exposure. Outcomes were assessed at 30 days and 365 days after STEMI and included all-cause mortality, stroke or transient ischemic attack (TIA), arrhythmia, thrombotic disorders, major adverse circulatory events (MACE), acute kidney injury (AKI), and cardiomyopathy. Results: At 365 days, C5-inhibited patients demonstrated significantly higher risks of death (21.7% vs. 15.8; p < 0.05), stroke/TIA (12.9% vs. 6.8%; p < 0.05), thrombotic disorders (23.8% vs. 11.3%; p < 0.001), MACE (36.8% vs. 22.8%; p < 0.001), and AKI (61.1% vs. 22.5%; p < 0.001). Cardiomyopathy rates were comparable between groups. Arrhythmia occurred less frequently in the C5-inhibition cohort (30.3% vs. 37.4%; p < 0.05). Similar patterns were observed at 30 days, with significantly increased risks for thrombotic disorders, MACE, and AKI in the C5-inhibited group. Hazard ratios confirmed elevated risks for most cardiovascular and thromboembolic outcomes at both time points. Conclusion: In this global real-world cohort, prior treatment with Eculizumab or Ravulizumab was associated with increased mortality and heightened cardiovascular and thromboembolic risk following STEMI. These findings underscore the need for careful clinical consideration of ongoing C5-inhibitor therapy in the acute management of STEMI and highlight the importance of prospective studies to clarify the mechanistic and clinical implications of complement blockade in acute myocardial ischemia.

Blockade of AT₁-receptors by telmisartan (TEL) has anti-atherosclerotic efficacy. We investigated to what extent the ACE2/Ang1-7/Mas axis-dependent mechanism contributes to the TEL-induced protection of endothelial function. Atherosclerosis was induced in C57BL/6 N, Mas-knock out (ko), and Ace2-ko mice by AAV-PCSK9^DY (2 ×10¹¹ VG) injections plus Western diet (WD) feeding (12w). Mice were treated (12w) with TEL or vehicle. Controls received no PCSK9^DY, chow-feeding, and vehicle-treatment. In the aortae of mice, the plaque burden was determined, RNAseq analyses were performed and functional properties were assessed by quantifying the mechanical properties of the endothelial surface by Atomic Force Microscopy. Regardless of strain, plaque burden and total cholesterol were increased upon AAV-PCSK9^DY+WD but decreased by TEL. Cortical stiffness was also enhanced in all strains by AAV-PCSK9^DY+WD but reduced under TEL only in the C57BL/6 N, while remaining still high in both knockout strains. Plasma NO negatively correlated with cortical stiffness in C57BL/6 N, but not in transgenic mice. TNFα plasma levels and aortic MMP12 expression was increased in PCSK9^DY/WD vehicle-treated controls and was normalized by TEL in C57BL/6 N but not in Mas-ko and Ace2-ko mice. We conclude that TEL-induced reduction of endothelial stiffness occurred only in the C57BL/6 N but not in the Mas-ko and Ace2-ko mice. We suggest that the protective TEL effect is partly due to an Ang(1-7)/ACE2/Mas axis mediated mechanism. Since Mmp12 has well-known proatherogenic properties but was not altered in the two transgenic mouse lines, follow-up studies are required to further elucidate the correlation between Mmp12 and the Ang(1-7)/ACE2/Mas axis with respect to atherosclerosis.