AIM2 Inflammasome Activation Contributes to Aortic Dissection in Sporadic Aortic Disease Mouse Model

2022 ◽  
Vol 272 ◽  
pp. 105-116
Author(s):  
Waleed Ageedi ◽  
Chen Zhang ◽  
William Case Frankel ◽  
Ashley Dawson ◽  
Yang Li ◽  
...  
Keyword(s):  
Aortic Dissection ◽  
Mouse Model ◽  
Aortic Disease ◽  
Inflammasome Activation

scholarly journals Alterations in the Gut-Microbial-Inflammasome-Brain Axis in a Mouse Model of Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 779
Author(s):  
Pradeep K. Shukla ◽  
David F. Delotterie ◽  
Jianfeng Xiao ◽  
Joseph F. Pierre ◽  
RadhaKrishna Rao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Gut Microbiota ◽  
Transgenic Mice ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Gut Barrier Function ◽  
Elevated Expression ◽  
5Xfad Mice

Alzheimer’s disease (AD), a progressive neurodegenerative disorder characterized by memory loss and cognitive decline, is a major cause of death and disability among the older population. Despite decades of scientific research, the underlying etiological triggers are unknown. Recent studies suggested that gut microbiota can influence AD progression; however, potential mechanisms linking the gut microbiota with AD pathogenesis remain obscure. In the present study, we provided a potential mechanistic link between dysbiotic gut microbiota and neuroinflammation associated with AD progression. Using a mouse model of AD, we discovered that unfavorable gut microbiota are correlated with abnormally elevated expression of gut NLRP3 and lead to peripheral inflammasome activation, which in turn exacerbates AD-associated neuroinflammation. To this end, we observe significantly altered gut microbiota compositions in young and old 5xFAD mice compared to age-matched non-transgenic mice. Moreover, 5xFAD mice demonstrated compromised gut barrier function as evident from the loss of tight junction and adherens junction proteins compared to non-transgenic mice. Concurrently, we observed increased expression of NLRP3 inflammasome and IL-1β production in the 5xFAD gut. Consistent with our hypothesis, increased gut–microbial–inflammasome activation is positively correlated with enhanced astrogliosis and microglial activation, along with higher expression of NLRP3 inflammasome and IL-1β production in the brains of 5xFAD mice. These data indicate that the elevated expression of gut–microbial–inflammasome components may be an important trigger for subsequent downstream activation of inflammatory and potentially cytotoxic mediators, and gastrointestinal NLRP3 may promote NLRP3 inflammasome-mediated neuroinflammation. Thus, modulation of the gut microbiota may be a potential strategy for the treatment of AD-related neurological disorders in genetically susceptible hosts.

Aortic Aneurysm

2018 ◽  
Author(s):  
Christine E Lee ◽  
Leily Naraghi ◽  
Beatrice Hoffmann
Keyword(s):  
Aortic Aneurysm ◽  
Aortic Dissection ◽  
Intramural Hematoma ◽  
Aortic Disease ◽  
Magnetic Resonance Images ◽  
Aortic Aneurysms ◽  
High Morbidity ◽  
Aortic Diseases ◽  
Decision Algorithm ◽  
Type B Dissection

Aortic diseases are relatively rare but are associated with high morbidity and mortality. Emergency physicians (EPs) should consider aortic disease in all patients with pain in the torso, particularly those with other diverse or seemingly unconnected complaints. This review summarizes the pathophysiology, stabilization and assessment, diagnosis and treatment, and disposition and outcomes for patients with abdominal aortic aneurysms (AAAs), thoracic aortic aneurysms (TAAs), and aortic dissection. Figures show a transverse image of an AAAs with a transmural hematoma, a three-dimensional computed tomographic angiogram (CTA) rendering of a thoracic aneurysm associated with a bicuspid aortic valve in the typical ascending aortic location, a chest x-ray film demonstrating prominent and blurred aortic knob due to TAA, acute aortic dissection subtypes, an electrocardiogram and transesophageal echocardiography of a patient with acute ascending aortic dissection, magnetic resonance images of a patient with dissection of the proximal descending aorta, CT representations of a type A dissection involving a dilated ascending aorta and a type B dissection involving the descending thoracic aorta, and a decision algorithm for evaluation and treatment of a suspected aortic dissection. Tables list normal aortic dimensions by CTA and echocardiography, average annual rate of expansion and rupture of AAA based on current diameter, and the etiology of TAA. Key words: AAA, aorta, aortic dissection, ascending aortic dissection, descending aortic dissection, intimal tear, intramural hematoma, thoracic aortic aneurysm

scholarly journals Development of a novel aortic dissection mouse model and evaluation of drug efficacy using in-vivo assays and database analyses

2018 ◽  
pp. 1
Author(s):  
Yuki Izawa-Ishizawa ◽  
Masaki Imanishi ◽  
Yoshito Zamami ◽  
Hiroki Toya ◽  
Tomoko Nagao ◽  
...  
Keyword(s):  
Aortic Dissection ◽  
Mouse Model ◽  
Drug Efficacy ◽  
In Vivo Assays

scholarly journals Oxytocin antagonism prevents pregnancy-associated aortic dissection in a mouse model of Marfan syndrome

2019 ◽  
Vol 11 (490) ◽  
pp. eaat4822 ◽  
Author(s):  
Jennifer Pardo Habashi ◽  
Elena Gallo MacFarlane ◽  
Rustam Bagirzadeh ◽  
Caitlin Bowen ◽  
Nicholas Huso ◽  
...  
Keyword(s):  
Aortic Dissection ◽  
Mouse Model ◽  
Marfan Syndrome ◽  
Uterine Contraction ◽  
Aortic Wall ◽  
Erk Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Erk Phosphorylation ◽  
Extracellular Signal ◽  
Erk Kinase

Women with Marfan syndrome (MFS) are at high risk for pregnancy-associated aortic dissection. Pathogenic models that singularly invoke hemodynamic stress are difficult to reconcile with predominant postnatal occurrence of aortic tear, often occurring weeks to months after delivery. In consideration of events that peak at term, are sustained after delivery, and might synergize with previously defined signaling pathways implicated in aneurysm progression, we examined the hormone oxytocin, which initiates uterine contraction and milk letdown for the duration of lactation through phosphorylation of extracellular signal–regulated kinase (ERK). In a mouse model of MFS that shows highly penetrant postnatal aortic dissection, risk was strongly attenuated by preventing lactation or use of an oxytocin receptor antagonist. Survival correlated inversely with the extent of ERK activation in the aortic wall, and strong protection was observed upon attenuation of ERK phosphorylation using an inhibitor of ERK kinase (MEK) or the U.S. Food and Drug Administration–approved medication hydralazine, offering potential therapeutic strategies for pregnancy-associated vascular catastrophe in the setting of MFS.

scholarly journals Nitric oxide mediates aortic disease in mice deficient in the metalloprotease Adamts1 and in a mouse model of Marfan syndrome

2017 ◽  
Vol 23 (2) ◽  
pp. 200-212 ◽  
Author(s):  
Jorge Oller ◽  
Nerea Méndez-Barbero ◽  
E Josue Ruiz ◽  
Silvia Villahoz ◽  
Marjolijn Renard ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mouse Model ◽  
Marfan Syndrome ◽  
Aortic Disease

scholarly journals Hydrogen sulfide inhibits NLRP3 inflammasome activation and reduces cytokine production bothin vitroand in a mouse model of inflammation

2017 ◽  
Vol 293 (7) ◽  
pp. 2546-2557 ◽  
Author(s):  
Mariela Castelblanco ◽  
Jérôme Lugrin ◽  
Driss Ehirchiou ◽  
Sonia Nasi ◽  
Isao Ishii ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
Mouse Model ◽  
Nlrp3 Inflammasome ◽  
Cytokine Production ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation

scholarly journals Inhibition of HIPK2 Alleviates Thoracic Aortic Disease in Mice With Progressively Severe Marfan Syndrome

2021 ◽  
Author(s):  
Cristina I. Caescu ◽  
Jens Hansen ◽  
Brittany Crockett ◽  
Wenzhen Xiao ◽  
Pauline Arnaud ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Aortic Aneurysm ◽  
Aortic Dissection ◽  
Marfan Syndrome ◽  
Thoracic Aortic Aneurysm ◽  
Acute Aortic Dissection ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Aortic Disease ◽  
Computational Analyses

Objective: Despite considerable research, the goal of finding nonsurgical remedies against thoracic aortic aneurysm and acute aortic dissection remains elusive. We sought to identify a novel aortic protein kinase that can be pharmacologically targeted to mitigate aneurysmal disease in a well-established mouse model of early-onset progressively severe Marfan syndrome (MFS). Approach and Results: Computational analyses of transcriptomic data derived from the ascending aorta of MFS mice predicted a probable association between thoracic aortic aneurysm and acute aortic dissection development and the multifunctional, stress-activated HIPK2 (homeodomain-interacting protein kinase 2). Consistent with this prediction, Hipk2 gene inactivation significantly extended the survival of MFS mice by slowing aneurysm growth and delaying transmural rupture. HIPK2 also ranked among the top predicted protein kinases in computational analyses of genes differentially expressed in the dilated aorta of 3 MFS patients, which strengthened the clinical relevance of the experimental finding. Additional in silico analyses of the human and mouse data sets identified the TGF (transforming growth factor)-β/Smad3 signaling pathway as a potential target of HIPK2 in the MFS aorta. Chronic treatment of MFS mice with an allosteric inhibitor of HIPK2-mediated stimulation of Smad3 signaling validated this prediction by mitigating thoracic aortic aneurysm and acute aortic dissection pathology and partially improving aortic material stiffness. Conclusions: HIPK2 is a previously unrecognized determinant of aneurysmal disease and an attractive new target for antithoracic aortic aneurysm and acute aortic dissection multidrug therapy.

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