murine-model-thoracic-aortic-dissection-induced-oral

Murine Model of Thoracic Aortic Dissection Induced by Oral &#946;-Aminopropionitrile and Subcutaneous Angiotensin II Infusion

Thoracic aortic dissection (TAD) is a highly fatal cardiovascular disease that lacks efficient medical treatment. Replication of animal models of TAD ...

Tianjin Medical University General Hospital

Coronary artery disease is one of the leading causes of death worldwide. Treatments including coronary artery intervention can cause complications, such as myocardial ischaemia-reperfusion injury (MIRI). Mitochondrial injury or dysfunction is a key pathology of MIRI. Mitochondrial transplantation is considered a promising therapeutic strategy for cardiac-related diseases, but its mechanism is still unclear. Nrf2 is a prominent player in supporting the structural and functional integrity of mitochondria. In our research, we focused on the effect of Nrf2 in the treatment of MIRI by mitochondrial transplantation. H9C2 cells were subjected to hypoxia/reoxygenation (H/R) and MIRI was induced in wild-type and Nrf2-/- mice by surgical ligation of the left coronary artery to elucidate the mechanism in vitro and in vivo, respectively. Exogenous mitochondria were extracted from healthy H9C2 cells and the pectoralis major and administered to H9C2 cells and mice with MIRI, respectively. Mitochondrial internalization, H9C2 cell injury or apoptosis, cardiac injury/function, mitochondrial function, morphology, mitochondrial dynamics, and the expression of components of the Nrf2 pathway were assessed. We found that exogenous mitochondria were internalized into H9C2 cardiomyocytes. Exogenous mitochondrial transplantation attenuated cardiomyocyte injury, cardiomyocyte apoptosis, and mitochondrial dysfunction. Exogenous mitochondrial transplantation increased the expression of Nrf2 and its downstream targets, attenuated cardiomyocyte injury, cardiac dysfunction, apoptosis, mitochondrial dysfunction, and mitochondrial fusion and fission imbalance, and improved mitophagy after MIRI in wild-type mice but not in Nrf2-/- mice. These results suggested that exogenous mitochondria can be internalized into cardiomyocytes and activate the Nrf2 pathway and that exogenous mitochondria improve cardiac function and ameliorate mitochondrial dysfunction via the Nrf2 pathway.

Nrf2 participates in the protective effect of exogenous mitochondria against mitochondrial dysfunction in myocardial ischaemic and hypoxic injury.

Subendothelial macrophage internalization of modified lipids and foam cell formation are hallmarks of atherosclerosis. Deubiquitinating enzymes (DUBs) are involved in various cellular activities; however, their role in foam cell formation is not fully understood. Here, using a loss-of-function lipid accumulation screening, we identified ubiquitin-specific peptidase 9 X-linked (USP9X) as a factor that suppressed lipid uptake in macrophages. We found that USP9X expression in lesional macrophages was reduced during atherosclerosis development in both humans and rodents. Atherosclerotic lesions from macrophage USP9X-deficient mice showed increased macrophage infiltration, lipid deposition, and necrotic core content than control apolipoprotein E-KO (Apoe-/-) mice. Additionally, loss-of-function USP9X exacerbated lipid uptake, foam cell formation, and inflammatory responses in macrophages. Mechanistically, the class A1 scavenger receptor (SR-A1) was identified as a USP9X substrate that removed the K63 polyubiquitin chain at the K27 site. Genetic or pharmacological inhibition of USP9X increased SR-A1 cell surface internalization after binding of oxidized LDL (ox-LDL). The K27R mutation of SR-A1 dramatically attenuated basal and USP9X knockdown-induced ox-LDL uptake. Moreover, blocking binding of USP9X to SR-A1 with a cell-penetrating peptide exacerbated foam cell formation and atherosclerosis. In this study, we identified macrophage USP9X as a beneficial regulator of atherosclerosis and revealed the specific mechanisms for the development of potential therapeutic strategies for atherosclerosis.

Disruption of USP9X in macrophages promotes foam cell formation and atherosclerosis.

Cardiac hypertrophy (CH) is a pathological phenotype of cardiomyopathy. Epigenetic modification is a mechanism associated with CH. Our study here investigated the histone demethylase KDM3C in relation to epigenetic regulation in CH. We found that KDM3C mRNA silencing alleviated CH, as evidenced by reduced ANP, BNP, and β-MHC mRNAs, increased α-MHC mRNA, decreased cell surface area, and reduced cellular protein/DNA ratios. Specifically, KDM3C upregulated miR-200c-3p expression through demethylation of H3K9me2, leading to enhanced binding of miR-200c-3p to GAS5 and suppression of GAS5 expression; these effects then led to reduced binding of GAS5 to miR-495-3p, increased miR-495-3p expression, and repression of PHF8 transcription. Through these mechanisms, our data indicate that KDM3C-dependent epigenetic modification promotes CH.

Histone demethylase KDM3C regulates the lncRNA GAS5-miR-495-3p-PHF8 axis in cardiac hypertrophy.

Fluid resuscitation is necessary to correct the sepsis-induced hypoperfusion, which is contradictory to the treatment of heart failure. This study explored the association between fluid balance (FB) of the first 24 h after ICU admission and mortality in critically ill patients with heart failure and sepsis.

Association between fluid balance and mortality for heart failure and sepsis: a propensity score-matching analysis.

The spleen contributes importantly to myocardial ischemia/reperfusion (MI/R) injury. Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) recruits inflammasomes, initiating inflammatory responses and mediating tissue injury. We hypothesize that myocardial cell-free DNA (cfDNA) activates the splenic NLRP3 inflammasome during early reperfusion, increases systemic inflammatory response, and exacerbates myocardial infarct. Mice were subjected to 40 min of ischemia followed by 0, 1, 5, or 15 min, or 24 h of reperfusion. Splenic leukocyte adoptive transfer was performed by injecting isolated splenocytes to mice with splenectomy performed prior to left coronary artery occlusion. CY-09 (4 mg/kg) was administered 5 min before reperfusion. During post-ischemic reperfusion, splenic protein levels of NLRP3, cleaved caspase-1, and interleukin-1β (IL-1β) were significantly elevated and peaked (2.1 ± 0.2-, 3.4 ± 0.4-, and 3.2 ± 0.2-fold increase respectively, p < 0.05) within 5 min of reperfusion. In myocardial tissue, NLRP3 was not upregulated until 24 h after reperfusion. Suppression by CY09, a specific NLRP3 inflammasome inhibitor, or deficiency of NLRP3 significantly reduced myocardial infarct size (17.3% ± 4.2% and 33.2% ± 1.8% decrease respectively, p < 0.01). Adoptive transfer of NLRP3 splenocytes to WT mice significantly decreased infarct size compared to transfer of WT splenocytes (19.1% ± 2.8% decrease, p < 0.0001). NLRP3 was mainly activated at 5 min after reperfusion in CD11b and LY6G splenocytes, which significantly increased during reperfusion (24.8% ± 0.7% vs.14.3% ± 0.6%, p < 0.0001). The circulating cfDNA level significantly increased in patients undergoing cardiopulmonary bypass (CPB) (43.3 ± 5.3 ng/mL, compared to pre-CPB 23.8 ± 3.5 ng/mL, p < 0.01). Mitochondrial cfDNA (mt-cfDNA) contributed to NLRP3 activation in macrophages (2.1 ± 0.2-fold increase, p < 0.01), which was inhibited by a Toll-like receptor 9(TLR9) inhibitor. The NLRP3 inflammasome in splenic monocytes is activated and mediates the inflammatory response shortly after reperfusion onset, exacerbating MI/R injury in mt-cfDNA/TLR9-dependent fashion. The schema reveals splenic NLRP3 mediates the inflammatory response in macrophages and exacerbates MI/R in a mitochondrial cfDNA/ TLR9-dependent fashion.

Splenic monocytes mediate inflammatory response and exacerbate myocardial ischemia/reperfusion injury in a mitochondrial cell-free DNA-TLR9-NLRP3-dependent fashion.

Hyperglycemia-a symptom that characterizes diabetes-is highly associated with atherothrombotic complications. However, the underlying mechanism by which hyperglycemia fuels platelet activation and arterial thrombus formation is still not fully understood.

Endothelial YAP Mediates Hyperglycemia-Induced Platelet Hyperactivity and Arterial Thrombosis.

Aberrant hepatic artery is particularly common, and its diversity and complexity play a critical role in surgery. The aim of this study was to describe the incidence and type of aberrant hepatic artery, and to compare differences in transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC) with vs without aberrant hepatic artery.

Retrospective Analysis of Aberrant Hepatic Artery in 1250 Patients with Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization.

This Mendelian randomization (MR) study aimed to explore the causal relationship between the genetic predisposition to type 2 diabetes mellitus (T2DM) and aortic dissection (AD), and to assess associations with genetically predicted glycemic traits. The study sought to verify the inverse relationship between T2DM and AD using a more robust and unbiased method, building on the observational studies previously established.

Genetic predisposition to type 2 diabetes mellitus and aortic dissection: a Mendelian randomisation study.

This study aims to investigate the associations between specific bacterial taxa of the gut microbiome and the development of aortic aneurysm diseases, utilizing Mendelian Randomization (MR) to explore these associations and overcome the confounding factors commonly present in observational studies.

Naishi Wu

Department of Cardiovascular Surgery

Tianjin Medical University General Hospital

Murine Model of Thoracic Aortic Dissection Induced by Oral β-Aminopropionitrile and Subcutaneous Angiotensin II Infusion

Naishi Wu

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Cardiovascular Surgery

Tianjin Medical University General Hospital

Murine Model of Thoracic Aortic Dissection Induced by Oral β-Aminopropionitrile and Subcutaneous Angiotensin II Infusion

Department of Cardiovascular Surgery