Biology subjects

Krueger, I.

Publications and source records attributed to Krueger, I..

3 recordsLinked to original sources

bioRxiv2024

Crosstalk between thrombospondin-1 and CD36 modulates platelet-RBC interaction limiting thrombosis and abdominal aneurysm formation

Red blood cells (RBCs) contribute to hemostasis and thrombosis by interaction with platelets via the FasL-FasR pathway to induce procoagulant activity and thrombin formation. Here, we identified a novel mechanism of platelet-RBC interaction via the CD36-thrombospondin-1 (TSP-1) signaling pathway, which is important in thrombus formation and the recruitment of RBCs to collagen-adherent platelets. Platelet-released TSP-1 can bind to CD36 at the RBC membrane to enhance procoagulant activity and to increase the activation of integrin IIb{beta}3, which represents an additional ligand for erythroid FasR, suggesting that both mechanisms of platelet-RBC interaction act in concert to propagate thrombus formation. In patients with abdominal aortic aneurysm (AAA), enhanced procoagulant activity of RBCs and platelets is accompanied by elevated exposure of TSP-1 and FasL at the platelet surface and accumulation of TSP-1 in the aortic wall and the intraluminal thrombus, suggesting that platelet-RBC interaction plays an important role in AAA pathology. TSP-1-deficient mice are protected against aortic diameter expansion in an experimental model of AAA, highlighting the crucial role of the CD36-TSP-1 axis in AAA. Thus, interfering with platelet-RBC interaction may be a promising therapeutic approach to reduce pro-coagulant activity and preserve AAA patients from surgery or rupture.

pathology↗

bioRxiv2023

Collagen receptor GPVI-mediated platelet activation and pro-coagulant activity aggravates inflammation and aortic wall remodelling in abdominal aortic aneurysm

Platelets play an important role in cardio- and cerebrovascular diseases. Abdominal aortic aneurysm (AAA) is a highly lethal, atherosclerotic-related disease with characteristic features of progressive dilatation of the abdominal aorta and degradation of the vessel wall accompanied by chronic inflammation. Platelet activation and pro-coagulant activity play a decisive role in the AAA pathology as they might trigger AAA development in both mice and men. The present study investigated the impact of the major platelet collagen receptor glycoprotein (GP)VI in cellular processes underlying AAA initiation and progression. Genetic deletion of GPVI offered protection of mice against aortic diameter expansion in experimental AAA. Mechanistically, GPVI deficiency resulted in decreased inflammation with reduced infiltration of neutrophils and platelets into the aortic wall. Further, remodelling of the aortic wall was improved in absence of GPVI, indicated by reduced MMP2/9 and OPN plasma levels and an enhanced -SMA content within the aortic wall, accompanied by reduced cell apoptosis. As a result, an elevation in intima/media thickness and elastin content were observed in GPVI-deficient PPE mice, coursing a significantly reduced aortic diameter expansion and reduced aneurysm incidence. In AAA patients, enhanced plasma levels of soluble GPVI and fibrin, besides fibrin accumulation within the intraluminal thrombus (ILT) suggested that GPVI might serve as a biomarker and mediator in fibrin-supported stabilization of the ILT. In conclusion, our results emphasize the potential need for a GPVI-targeted anti-platelet therapy to reduce AAA initiation and progression, as well as to protect AAA patients from aortic rupture. Translational perspectiveAbdominal aortic aneurysm (AAA) is an atherosclerotic-related, cardiovascular disease (CVD) with high mortality. The impact of platelets in different cellular processes underlying AAA initiation and progression remains unclear.Therefore, we analysed the role of the major platelet collagen receptor GPVI in the pathogenesis of AAA. Results from platelet depleted mice and patients with AAA revealed a significant contribution of GPVI to the inflammatory response and remodelling process of the aorta. Further, elevated accumulation of fibrin, a recently identified ligand of GPVI in the intraluminal thrombus (ILT) and in the plasma of AAA patients, suggests that GPVI binding to fibrin plays a role in ILT formation and probably stabilization of the abdominal aorta. Furthermore, increased levels of sGPVI suggest that GPVI might serve as a clinical biomarker for AAA. Thus, therapeutic targeting of GPVI-mediated platelet activation might be an effective anti-thrombotic strategy for AAA patients.

cell biology↗

bioRxiv2022

Platelets modulate inflammation and matrix remodeling in abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is a highly lethal disease with progressive dilatation of the abdominal aorta accompanied by degradation and remodelling of the vessel wall due to chronic inflammation. Platelets play an important role in cardiovascular diseases but their role in AAA is poorly understood. The present study revealed that platelets play a crucial role in promoting AAA through modulation of inflammation and degradation of the ECM. They are responsible for the up-regulation of SPP1 (osteopontin, OPN) gene expression in macrophages and aortic tissue, which triggers inflammation and remodeling but also platelet adhesion and migration into the abdominal aortic wall and the intraluminal thrombus (ILT). Further, enhanced platelet activation and pro-coagulant activity results in elevated gene expression of various cytokines, Mmp9 and Col1a1 in macrophages and Il-6 and Mmp9 in fibroblasts. Enhanced platelet activation and pro-coagulant activity was also detected in AAA patients. Further, we detected platelets and OPN in the vessel wall and in the ILT of patients who underwent open repair of AAA. Platelet depletion in experimental murine AAA reduced inflammation and ECM remodeling, with reduced elastin fragmentation and aortic diameter expansion. Of note, OPN co-localized with platelets, suggesting a potential role of OPN for the recruitment of platelets into the ILT and the aortic wall. In conclusion, our data strongly supports the potential relevance of anti-platelet therapy to reduce AAA progression and rupture in AAA patients. Translational perspectiveAbdominal aortic aneurysm (AAA) is a severe cardiovascular disease (CVD) with high mortality. Since the role of platelets is unclear, we explored platelet-mediated processes in the pathogenesis of AAA. Results from platelet depleted mice and patients with AAA revealed that platelets modulate inflammatory and stiffness-related gene expression of macrophages and fibroblasts. Further, platelets induce the release of osteopontin important for the recruitment of platelets to the aortic wall and to the intraluminal thrombus (ILT). Consequently, platelet depletion significantly reduced aneurysm growth. Thus, therapeutic targeting of platelet activation might be crucial for the treatment of patients to reduce AAA formation and progression.

molecular biology↗