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.

Platelets regulate ischemia-induced revascularization and angiogenesis by secretion of growth factor-modulating factors.

In ischemic tissue, platelets can modulate angiogenesis. The specific factors influencing this function, however, are poorly understood. Here, we characterized the complement anaphylatoxin C5a-mediated activation of C5a receptor 1 (C5aR1) expressed on platelets as a potent regulator of ischemia-driven revascularization.

Protocol to isolate and analyze mouse bone marrow derived dendritic cells (BMDC).

Different types of immune cells are involved in atherogenesis and may act atheroprotective or atheroprogressive. Here, we describe an in vitro approach to analyze CD11c cells and CD11c-derived ApoE in atherosclerosis. The major steps include harvesting mouse bone marrow, plating cells in culture dishes, treating them with differentiation factors, and collecting cells after removal of undesirable populations.

Activated Platelets Upregulate β Integrin Mac-1 (CD11b/CD18) on Dendritic Cells, Which Mediates Heterotypic Cell-Cell Interaction.

Recent evidence suggests interaction of platelets with dendritic cells (DCs), while the molecular mechanisms mediating this heterotypic cell cross-talk are largely unknown. We evaluated the role of integrin Mac-1 (αMβ2, CD11b/CD18) on DCs as a counterreceptor for platelet glycoprotein (GP) Ibα. In a dynamic coincubation model, we observed interaction of human platelets with monocyte-derived DCs, but also that platelet activation induced a sharp increase in heterotypic cell binding.

Apolipoprotein E derived from CD11c cells ameliorates atherosclerosis.

Atherosclerosis is studied in models with dysfunctional lipid homeostasis-predominantly the ApoE mouse. The role of antigen-presenting cells (APCs) for lipid homeostasis is not clear. Using a LacZ reporter mouse, we showed that CD11c cells were enriched in aortae of ApoE mice.

Inflammation in Metabolic and Cardiovascular Disorders-Role of Oxidative Stress.

Cardiovascular diseases (CVD) constitute the main cause of death worldwide. Both inflammation and oxidative stress have been reported to be involved in the progress of CVD. It is well known that generation of oxidative stress during the course of CVD is involved in tissue damage and inflammation, causing deleterious effects such as hypertension, dysfunctional metabolism, endothelial dysfunction, stroke, and myocardial infarction.

The C5a/C5a receptor 1 axis controls tissue neovascularization through CXCL4 release from platelets.

Platelets contribute to the regulation of tissue neovascularization, although the specific factors underlying this function are unknown. Here, we identified the complement anaphylatoxin C5a-mediated activation of C5a receptor 1 (C5aR1) on platelets as a negative regulatory mechanism of vessel formation. We showed that platelets expressing C5aR1 exert an inhibitory effect on endothelial cell functions such as migration and 2D and 3D tube formation.

Complement, inflammation and thrombosis.

A mutual relationship exists between immune activation and mechanisms of thrombus formation. In particular, elements of the innate immune response such as the complement system can modulate platelet activation and subsequently thrombus formation. Several components of the complement system including C3 or the membrane attack complex have been reported to be associated with platelets and become functionally active in the micromilieu of platelet activation.

Platelets as Mediators of Neuroinflammation and Thrombosis.

Beyond platelets function in hemostasis, there is emerging evidence to suggest that platelets contribute crucially to inflammation and immune responses. Therefore, considering the detrimental role of inflammatory conditions in severe neurological disorders such as multiple sclerosis or stroke, this review outlines platelets involvement in neuroinflammation. For this, distinct mechanisms of platelet-mediated thrombosis and inflammation are portrayed, focusing on the interaction of platelet receptors with other immune cells as well as brain endothelial cells.

Platelets as therapeutic targets to prevent atherosclerosis.

Cardiovascular disease remains the main cause of death worldwide. For this reason, strategies for the primary prevention of atherosclerosis and atherosclerosis-related pathologies like stroke or myocardial infarction are needed. Platelets are key players of atherosclerosis-related vascular thrombotic pathologies and their role as targets in secondary prevention of atherosclerosis-related complications is uncontested.

Conventional echocardiographic parameters or three-dimensional echocardiography to evaluate right ventricular function in percutaneous edge-to-edge mitral valve repair (PMVR).

Introduction: In this study, we evaluated right ventricular (RV) function before and after percutaneous mitral valve repair (PMVR) using conventional echocardiographic parameters and novel 3DE data sets acquired prior to and directly after the procedure.

Patients And Methods: Observational study on 45 patients undergoing PMVR at an university hospital.

Results: In the overall collective, the 3D RV-EF before and after PMVR showed no significant change (p = 0.

Platelets and Immune Responses During Thromboinflammation.

Besides mediating hemostatic functions, platelets are increasingly recognized as important players of inflammation. Data from experiments in mice and men revealed various intersection points between thrombosis, hemostasis, and inflammation, which are addressed and discussed in this review in detail. One such example is the intrinsic coagulation cascade that is initiated after platelet activation thereby further propagating and re-enforcing wound healing or thrombus formation but also contributing to the pathophysiology of severe diseases.

Elevated Mitral Valve Pressure Gradient Is Predictive of Long-Term Outcome After Percutaneous Edge-to-Edge Mitral Valve Repair in Patients With Degenerative Mitral Regurgitation ( MR ), But Not in Functional MR.

Background This study analyzed the effects on long-term outcome of residual mitral regurgitation ( MR ) and mean mitral valve pressure gradient ( MVPG ) after percutaneous edge-to-edge mitral valve repair using the MitraClip system. Methods and Results Two hundred fifty-five patients who underwent percutaneous edge-to-edge mitral valve repair were analyzed. Kaplan-Meier and Cox regression analyses were performed to evaluate the impact of residual MR and MVPG on clinical outcome.

Functional Relevance of the Anaphylatoxin Receptor C3aR for Platelet Function and Arterial Thrombus Formation Marks an Intersection Point Between Innate Immunity and Thrombosis.

Background: Platelets have distinct roles in the vascular system in that they are the major mediator of thrombosis, critical for restoration of tissue integrity, and players in vascular inflammatory conditions. In close spatiotemporal proximity, the complement system acts as the first line of defense against invading microorganisms and is a key mediator of inflammation. Whereas the fluid phase cross-talk between the complement and coagulation systems is well appreciated, the understanding of the pathophysiological implications of such interactions is still scant.

Complement links platelets to innate immunity.

The complement system is a versatile part of our immune system. Various intersection points of complement with other cells and molecules of the immune response are well described. Platelets are classically conceived as cells of hemostasis.

Platelet bound oxLDL shows an inverse correlation with plasma anaphylatoxin C5a in patients with coronary artery disease.

Both oxidized lipids as well as the complement system contribute to atherothrombosis. The expression of complement receptors correlates with the expression of platelet activation markers, and platelet bound oxidized low-density lipoprotein (oxLDL) modulates platelet function. In the present study, we investigated the relationship of markers of complement activation, the anaphylatoxins C5a and C3a, and oxidized low-density lipoprotein.

Platelets in inflammation and atherogenesis.

Platelets contribute to processes beyond thrombus formation and may play a so far underestimated role as an immune cell in various circumstances. This review outlines immune functions of platelets in host defense, but also how they may contribute to mechanisms of infectious diseases. A particular emphasis is placed on the interaction of platelets with other immune cells.