Objective: The thrombolytic therapy drug, Reteplase, is a domain deletion mutant of tissue plasminogen activator (tPA), comprising the kringle 2 and protease (K2P) domains. Some kringle domains of hemostatic proteins are antiangiogenic and promote apoptosis. The objective of this study was to investigate whether K2P is an angiogenesis inhibitor because of the presence of kringle 2.
Methods And Results: K2P inhibited basic fibroblast growth factor-induced human endothelial cell proliferation and migration. Inhibition was not dependent on the protease activity of K2P because similar results were obtained with catalytically inactivated K2P. Purification of the kringle 2 domain derived from elastase cleavage of K2P at the Arg275-Ile276 bond revealed that inhibition was mediated by this domain. In addition, K2P inhibited angiogenesis in vivo and increased endothelial cell apoptosis.
Conclusions: Wound healing and angiogenesis are severely compromised by K2P. These data provide new mechanistic insights into the bleeding complications observed in some patients while undergoing thrombolytic therapy with this drug. In addition, we identify the kringle 2 domain of tPA as a novel target for antiangiogenic therapy.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1161/01.ATV.0000157980.15710.2b | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Accurate evaluation of factor VIII activity of efanesoctocog alfa in the presence of emicizumab.
J Thromb Haemost
January 2025
Centre de Référence de l'Hémophilie, Hospices Civils de Lyon, UR4609 Universite Claude Bernard Lyon 1, Lyon, France. Electronic address:
Background: Efanesoctocog is a B-domain-deleted, Fc-fusion FVIII linked to the D'D3 domain of VWF and two XTEN polypeptides, designed for an ultra-extended half-life for prophylaxis in hemophilia A, but also aiding in managing acute bleeding or surgery in patients on long-term emicizumab. However, no current laboratory method accurately measures FVIII levels in the presence of emicizumab. We hypothesized that the chromogenic (CSA) FVIII assay, specifically calibrated for efanesoctocog using bovine coagulation factors, could provide an accurate assessment of efanesoctocog activity.
View Article and Find Full Text PDFMink enteritis virus infection induced cell cycle arrest and autophagy for its replication.
Vet Microbiol
January 2025
Shandong Provincial Key Laboratory of Zoonoses, Shandong Agricultural University, Taian, Shandong Province 271018, China; College of Veterinary Medicine, Shandong Agricultural University, Taian, Shandong Province 271018, China. Electronic address:
Mink enteritis virus (MEV) is an important pathogen causing mink viral enteritis. The mechanisms of cell cycle arrest induced by MEV infection and the roles of autophagy in MEV replication remain unclear. In this study, the roles of MEV NS1 protein in inducing cell cycle arrest were investigated, using the in vitro CRFK cell models.
View Article and Find Full Text PDFAstrocytic NLRP3 cKO mitigates depression-like behaviors induced by mild TBI in mice.
Neurobiol Dis
January 2025
Department of Anesthesiology, Hebei Province, Cangzhou Hospital of Integrated Traditional and Western Medicine, Cangzhou, China,. Electronic address:
Background: Reports indicate that depression is a common mental health issue following traumatic brain injury (TBI). Our prior research suggests that Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-related neuroinflammation, modulated by glial cells such as astrocytes, is likely to play a crucial role in the progression of anxiety and cognitive dysfunction. However, there is limited understanding of the potential of astrocytic NLRP3 in treating depression under mild TBI condition.
View Article and Find Full Text PDFFunctions of the Bloom Syndrome Helicase N-terminal Intrinsically Disordered Region.
Genetics
January 2025
Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Bloom Syndrome helicase (Blm) is a RecQ family helicase involved in DNA repair, cell-cycle progression, and development. Pathogenic variants in human BLM cause the autosomal recessive disorder Bloom Syndrome, characterized by predisposition to numerous types of cancer. Prior studies of Drosophila Blm mutants lacking helicase activity or protein have shown sensitivity to DNA damaging agents, defects in repairing DNA double-strand breaks (DSBs), female sterility, and improper segregation of chromosomes in meiosis.
View Article and Find Full Text PDFSevere neonatal hypotonia due to variant affecting function of ZnT5 zinc transporter.
JIMD Rep
January 2025
The Morris Kahn Laboratory of Human Genetics, Faculty of Health Sciences Ben Gurion University Beer-Sheva Israel.
The tightly-regulated spatial and temporal distribution of zinc ion concentrations within cellular compartments is controlled by two groups of Zn transporters: the 14-member ZIP/SLC39 family, facilitating Zn influx into the cytoplasm from the extracellular space or intracellular organelles; and the 10-member ZnT/SLC30 family, mobilizing Zn in the opposite direction. Genetic aberrations in most zinc transporters cause human syndromes. Notably, previous studies demonstrated osteopenia and male-specific cardiac death in mice lacking the ZnT5/ zinc transporter, and suggested association of two homozygous frameshift variants with perinatal mortality in humans, due to hydrops fetalis and hypertrophic cardiomyopathy.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!