establishment-minimally-invasive-rat-model-pulmonary-embolism-using

Establishment of a Minimally Invasive Rat Model of Pulmonary Embolism Using Autologous Blood Clots

Pulmonary embolism (PE) is one of the leading causes of cardiovascular death, resulting in a significant socioeconomic burden. Although current treatments ...

Chinese Academy of Medical Sciences

Graduate School of Chinese Academy of Medical Sciences & Peking Union Medical College

Varicose veins are found to be associated with increased risk of venous thromboembolism (VTE) in many observational studies, but whether varicose veins are causally associated with VTE remains unclear. Therefore, we used a series of Mendelian randomization (MR) methods to investigate that association.

Varicose Veins and Risk of Venous Thromboembolic Diseases: A Two-Sample-Based Mendelian Randomization Study.

Takayasu arteritis (TA) is a chronic granulomatous vasculitis involving in the main branches of aorta. Previous studies mainly used peripheral blood and some vascular tissues but seldom studies have sequenced vascular tissues. Here in this study, we aimed to explore the alterations of mRNA in TA by performing bulk RNA sequencing. A total of 14 abdominal aortic tissues including 8 from renal transplantation and 6 from patient with TA undergoing bypass surgeries. Bulk RNA sequencing were performed and after the quality control, a total of 1897 transcripts were observed to be significantly differently ( < 0.05 and LogFC > 1) expressed between the TA and control group, among which 1,361 transcripts were in TA group and 536 in the Control group. Reactome Pathway Enrichment Comparison analysis revealed interleukin-10 signaling and signaling by interleukins were highly expressed in TA group. Besides, extracellular matrix organization was also observed in this group. WGCNA and PPI obtained 26 core genes which were highly correlated with the clinical phenotype. We then also perform deconvolution of the bulk RNA-seq data by using the scRNA-seq dataset and noticed the high proportion of smooth muscle cells in our dataset. Additionally, immunohistochemical staining confirmed our bioinformatic analysis that TA aortic tissues express high levels of IL-1R1 and IL-1R2. Briefly, this study revealed critical roles of interleukins in TA pathogenesis, and SMCs may also participate in the reconstruction in vessel wall at late stage of TA.

Transcriptome profiling of abdominal aortic tissues reveals alterations in mRNAs of Takayasu arteritis.

Germinal matrix hemorrhage (GMH) is a devasting neurological disease in premature newborns. After GMH, brain iron overload associated with hemoglobin degradation contributed to oxidative stress, causing disruption of the already vulnerable blood-brain barrier (BBB). Mitochondrial ferritin (FTMT), a novel mitochondrial outer membrane protein, is crucial in maintaining cellular iron homeostasis. We aimed to investigate the effect of FTMT upregulation on oxidative stress and BBB disruption associated with brain iron overload in rats. A total of 222 Sprague-Dawley neonatal rat pups (7 days old) were used to establish a collagenase-induced GMH model and an iron-overload model of intracerebral FeCl injection. Deferiprone was administered via gastric lavage 1 h after GMH and given daily until euthanasia. FTMT CRISPR Knockout and adenovirus (Ad)-FTMT were administered intracerebroventricularly 48 h before GMH and FeCl injection, respectively. Neurobehavioral tests, immunofluorescence, Western blot, Malondialdehyde measurement, and brain water content were performed to evaluate neurobehavior deficits, oxidative stress, and BBB disruption, respectively. The results demonstrated that brain expressions of iron exporter Ferroportin (FPN) and antioxidant glutathione peroxidase 4 (GPX4) as well as BBB tight junction proteins including Claudin-5 and Zona Occulta (ZO)-1 were found to be decreased at 72 h after GMH. FTMT agonist Deferiprone attenuated oxidative stress and preserved BBB tight junction proteins after GMH. These effects were partially reversed by FTMT CRISPR Knockout. Iron overload by FeCl injection resulted in oxidative stress and BBB disruption, which were improved by Ad-FTMT mediated FTMT overexpression. Collectively, FTMT upregulation is neuroprotective against brain injury associated with iron overload. Deferiprone reduced oxidative stress and BBB disruption by maintaining cellular iron homeostasis partially by the upregulating of FTMT after GMH. Deferiprone may be an effective treatment for patients with GMH.

Mitochondrial ferritin upregulation reduced oxidative stress and blood-brain-barrier disruption by maintaining cellular iron homeostasis in a neonatal rat model of germinal matrix hemorrhage.

Ferroptosis contributes to brain injury after germinal matrix hemorrhage (GMH). Mitochondrial ferritin (FTMT), a novel mitochondrial outer membrane protein, reduces oxidative stress in neurodegenerative diseases. In vitro, Deferiprone has been shown to upregulate FTMT. However, the effects of FTMT upregulation by Deferiprone on neuronal ferroptosis after GMH and its underlying mechanism has not been investigated. In our study, 389 Sprague-Dawley rat pups of postnatal day 7 were used to establish a collagenase-induced GMH model and an iron-overload model of intracerebral FeCl injection. The brain expressions of FTMT, N-myc downstream-regulated gene-1 (NDGR1), Yes-associated protein (YAP), ferroptosis-related molecules including transferrin receptor (TFR) and acyl-CoA synthase long-chain family member 4 (ACSL4) were increased after GMH. FTMT agonist Deferiprone improved neurological deficits and hydrocephalus after GMH. Deferiprone or Adenovirus-FTMT enhanced YAP phosphorylation at the Ser site and attenuated ferroptosis, which was reversed by NDRG1 CRISPR Knockout. Iron overload induced neuronal ferroptosis and neurological deficits, which were improved by YAP CRISPR Knockout. Collectively, FTMT upregulation by Deferiprone reduced neuronal ferroptosis and neurological deficits via the NDRG1/YAP signaling pathway after GMH. Deferiprone may serve as a potential non-invasive treatment for GMH patients.

Mitochondrial ferritin upregulation by deferiprone reduced neuronal ferroptosis and improved neurological deficits via NDRG1/Yap pathway in a neonatal rat model of germinal matrix hemorrhage.

Ruihao Li

Department of Vascular Surgery,
Beijing Hospital,
National Center of Gerontology,
Institute of Geriatric medicine,
Department of Vascular Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine

Chinese Academy of Medical Sciences

Establishment of a Minimally Invasive Rat Model of Pulmonary Embolism Using Autologous Blood Clots