Dataset Information

Targeting Platelet Activation in Abdominal Aortic Aneurysm: Current Knowledge and Perspectives.

ABSTRACT: Abdominal aortic aneurysm (AAA) is a potentially fatal vascular disease that involves complex multifactorial hemodynamic, thrombotic, inflammatory, and aortic wall remodeling processes. However, its mechanisms are incompletely understood. It has become increasingly clear that platelets are involved in pathological processes of vascular diseases beyond their role in hemostasis and thrombosis. Platelet activation with membrane receptors and secreted mediators promotes thrombus formation and the accumulation of inflammatory cells, which may play an important role in the development of AAA by destroying the structural integrity and stability of the vessel wall. Turbulent blood flow in aortic aneurysms promotes platelet activation and aggregation. Platelet count and heterogeneity are important predictive, diagnostic, and prognostic indicators of AAA. We summarize the relationship between platelet activation and AAA development and propose future research directions and possible clinical applications.

SUBMITTER: Sun W

PROVIDER: S-EPMC8961578 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Targeting Platelet Activation in Abdominal Aortic Aneurysm: Current Knowledge and Perspectives.

Sun Weiliang W Zheng Jingang J Gao Yanxiang Y

Biomolecules 20220125 2

Abdominal aortic aneurysm (AAA) is a potentially fatal vascular disease that involves complex multifactorial hemodynamic, thrombotic, inflammatory, and aortic wall remodeling processes. However, its mechanisms are incompletely understood. It has become increasingly clear that platelets are involved in pathological processes of vascular diseases beyond their role in hemostasis and thrombosis. Platelet activation with membrane receptors and secreted mediators promotes thrombus formation and the ac ...[more]

PMID: 35204706

Similar Datasets

Project description:Abdominal aortic aneurysm (AAA) is a common disease and highly lethal if untreated. The progressive dilatation of the abdominal aorta is accompanied by degradation and remodeling of the vessel wall due to chronic inflammation. Pannexins represent anion-selective channels and play a crucial role in non-vesicular ATP release to amplify paracrine signaling in cells. Thus, pannexins are involved in many (patho-) physiological processes. Recently, Panx1 channels were identified to be significantly involved in abdominal aortic aneurysm formation through endothelial derived Panx1 regulated inflammation and aortic remodeling. In platelets, Panx1 becomes activated following activation of glycoprotein (GP) VI. Since platelets play a role in cardiovascular diseases including abdominal aortic aneurysm, we analyzed the contribution of platelet Panx1 in the progression of abdominal aortic aneurysm. We detected enhanced Panx1 plasma levels in abdominal aortic aneurysm patients. In experimental abdominal aortic aneurysm using the pancreatic porcine elastase (PPE) mouse model, a major contribution of platelet Panx1 channels in platelet activation, pro-coagulant activity of platelets and platelet-mediated inflammation has been detected. In detail, platelets are important for the migration of neutrophils into the aortic wall induced by direct cell interaction and by activation of endothelial cells. Decreased platelet activation and inflammation did not affect ECM remodeling or wall thickness in platelet-specific Panx1 knock-out mice following PPE surgery. Thus, aortic diameter expansion at different time points after elastase infusion of the aortic wall was unaltered in platelet-specific Panx1 deficient mice suggesting that the modulation of inflammation alone does not affect abdominal aortic aneurysm formation and progression. In conclusion, our data strongly supports the role of platelets in inflammatory responses in abdominal aortic aneurysm via Panx1 channels and adds important knowledge about the significance of platelets in abdominal aortic aneurysm pathology important for the establishment of an anti-platelet therapy for abdominal aortic aneurysm patients.

Project description:BackgroundMacrophage activation plays a critical role in abdominal aortic aneurysm (AAA) development. However, molecular mechanisms controlling macrophage activation and vascular inflammation in AAA remain largely unknown. The objective of the study was to identify novel mechanisms underlying adenosine deaminase acting on RNA (ADAR1) function in macrophage activation and AAA formation.MethodsAortic transplantation was conducted to determine the importance of nonvascular ADAR1 in AAA development/dissection. Ang II (Angiotensin II) infusion of ApoE-/- mouse model combined with macrophage-specific knockout of ADAR1 was used to study ADAR1 macrophage-specific role in AAA formation/dissection. The relevance of macrophage ADAR1 to human AAA was examined using human aneurysm specimens. Moreover, a novel humanized AAA model was established to test the role of human macrophages in aneurysm formation in human arteries.ResultsAllograft transplantation of wild-type abdominal aortas to ADAR1+/- recipient mice significantly attenuated AAA formation, suggesting that nonvascular ADAR1 is essential for AAA development. ADAR1 deficiency in hematopoietic cells decreased the prevalence and severity of AAA while inhibited macrophage infiltration and aorta wall inflammation. ADAR1 deletion blocked the classic macrophage activation, diminished NF-κB (nuclear factor kappa B) signaling, and enhanced the expression of a number of anti-inflammatory microRNAs. Mechanistically, ADAR1 interacted with Drosha to promote its degradation, which attenuated Drosha-DGCR8 (DiGeorge syndrome critical region 8) interaction, and consequently inhibited pri- to pre-microRNA processing of microRNAs targeting IKKβ, resulting in an increased IKKβ (inhibitor of nuclear factor kappa-B) expression and enhanced NF-κB signaling. Significantly, ADAR1 was induced in macrophages and interacted with Drosha in human AAA lesions. Reconstitution of ADAR1-deficient, but not the wild type, human monocytes to immunodeficient mice blocked the aneurysm formation in transplanted human arteries.ConclusionsMacrophage ADAR1 promotes aneurysm formation in both mouse and human arteries through a novel mechanism, that is, Drosha protein degradation, which inhibits the processing of microRNAs targeting NF-kB signaling and thus elicits macrophage-mediated vascular inflammation in AAA.

Dataset Information

Targeting Platelet Activation in Abdominal Aortic Aneurysm: Current Knowledge and Perspectives.

Publications

Targeting Platelet Activation in Abdominal Aortic Aneurysm: Current Knowledge and Perspectives.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets