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Journal of Thoracic Disease Jun 2021The aim of this study was to investigate the effects of beta-aminopropionitrile (BAPN) on the arterial walls of rodents, and to analyze the gross or pathological changes...
BACKGROUND
The aim of this study was to investigate the effects of beta-aminopropionitrile (BAPN) on the arterial walls of rodents, and to analyze the gross or pathological changes of arterial and other tissues of rodents treated with BAPN at different concentrations or doses.
METHODS
Eighteen SPF SD rats (4-5-week old) were divided into three groups: SD-0.2 (Group A), SD-0.4 (Group B), and SD-0.6 (Group C). The groups A, B and C were given 0.2%, 0.4%, and 0.6% BAPN solution, respectively, as drinking water for seven weeks. Forty SPF C57BL/6 mice (3-week old) were randomly divided into four groups: C57-0.2 (Group D), C57-0.4 (Group E), C57-0.6 (Group F) and the control group and given 0.2%, 0.4%, or 0.6% BAPN or distilled water as drinking water, respectively, for seven weeks. All experimental animals were free to drink water. The aortas were dissected and visually examined. At the same time, hematoxylin and eosin (HE) staining was performed in aorta tissue. The vascular diameter and area of the middle membrane were measured with IPP (Image-Pro Plus 6.0).
RESULTS
BAPN treatment significantly affected the water intake and weight gain of rats and mice. BAPN also caused thickening of the membrane in the aortas of rats and mice, and irregularity in the arrangement of elastic fibers. These pathological changes are similar to the pathological changes observed in human aneurysms. The incidence of dissecting aneurysm in C57 mice was higher than that of Sprague Dawley (SD) rats.
CONCLUSIONS
BAPN at a concentration of 0.4% was feasible to produce an animal model of dissecting aneurysm. In SD rats, the rate of pathological changes and other complications, such as intestinal rupture and scoliosis, was higher than the rates of dissecting aneurysm.
PubMed: 34277056
DOI: 10.21037/jtd-21-605 -
Journal of the American Heart... Jun 2021Background Aortic dissection (AD) is one of the most life-threatening cardiovascular diseases that exhibit high genetic heterogeneity. However, it is unclear whether...
Background Aortic dissection (AD) is one of the most life-threatening cardiovascular diseases that exhibit high genetic heterogeneity. However, it is unclear whether variants within the gene can cause AD. Therefore, we intend to determine whether is a causative gene of AD. Methods and Results We performed targeted sequencing in 702 patients with unrelated sporadic AD and 163 matched healthy controls using a predesigned panel with 152 vessel matrix-related genes. As a result, we identified that 11 variants in caused AD in 11 out of the 702 patients with AD. Furthermore, knockout () rats were generated through the CRISPR/Cas9 system. Although there was no spontaneous AD, electron microscopy revealed a fracture of elastic fibers and disarray of collagenous fibers in 6-week-old rats, but not in WT rats (93.3% versus 0.0%, <0.001). Three-week-old rats were used to induce the AD phenotype with β-aminopropionitrile monofumarate for 4 weeks followed by angiotensin II for 72 hours. The β-aminopropionitrile monofumarate and angiotensin II-treated rat model confirmed that rats had considerably higher AD incidence than WT rats. Subsequent mechanism analyses demonstrated that the transforming growth factor-β-signaling pathway was significantly activated in rats. Conclusions Our findings, for the first time, revealed a relationship between variants in and AD via targeted sequencing in 1.57% patients with sporadic aortic dissection. The knockout rats exhibited AD after an intervention, indicating that is a causative gene of AD. Activation of the transforming growth factor-β-signaling pathway may be implicated in the pathogenesis of this kind of AD.
Topics: Aortic Dissection; Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Blotting, Western; Collagen Type V; DNA; Disease Models, Animal; Female; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Male; Microscopy, Electron; Middle Aged; Phenotype; Rats; Rats, Transgenic; Retrospective Studies; Signal Transduction; Tomography, X-Ray Computed; Transforming Growth Factor beta
PubMed: 34041919
DOI: 10.1161/JAHA.120.019276 -
The Journal of Thoracic and... Dec 2013Although systemic hypertension is closely associated with aortic aneurysm (AA) formation, there are many patients with AA without hypertension. In these patients, an...
BACKGROUND
Although systemic hypertension is closely associated with aortic aneurysm (AA) formation, there are many patients with AA without hypertension. In these patients, an inflammation-mediated progression of aneurysmal disease is likely responsible for AA growth and eventual rupture. Unfortunately, there remains no reproducible and durable small animal model of aortic aneurysmal disease, the development of which would enable the investigation of the pathophysiology of this vexing condition. The first aim was to establish a useful wild-type mouse model of AA with low mortality. The second aim was to use this model to assess the protective effect of azelnidipine, a new calcium channel blocker, against the progression of the AA independent of its antihypertensive effect.
METHODS
Angiotensin II and β-aminopropionitrile (a lysyl oxidase inhibitor) were administrated subcutaneously in 7-week-old C57BL/6J mice using an osmotic minipump for 4 weeks to generate a wild-type mouse model of AA. Concurrently, azelnidipine (a calcium channel blocker) or a placebo was administrated orally for 4 weeks. Mice were humanely killed and assessed at the end of the 4 weeks of pharmacologic manipulation.
RESULTS
The combined infusion of angiotensin II and β-aminopropionitrile induced degenerative aneurysm of the thoracic and/or abdominal aorta (11/12; 92%). The majority of aneurysms were located in the distal aortic arch and suprarenal abdominal aorta. Although there was no difference in systolic blood pressure between the control and azelnidipine-treated groups, azelnidipine significantly reduced the incidence of AA (2/11; 18%). Azelnidipine treatment reduced the pathologic findings normally associated with aneurysm formation within the aortic wall. Azelnidipine also reduced the number of macrophage antigen-3 (MAC-3)-positive cells in the periaortic adipose tissue and reduced the gene expression levels of tumor necrosis factor-alpha and matrix metalloproteinase-2 and -9 within the aortic wall.
CONCLUSIONS
This study demonstrates that combined treatment with angiotensin II and β-aminopropionitrile induces degenerative AAs in wild-type mice, and azelnidipine prevents aneurysm progression via its anti-inflammatory effect.
Topics: Aminopropionitrile; Angiotensin II; Animals; Anti-Inflammatory Agents; Aorta, Abdominal; Aorta, Thoracic; Aortic Aneurysm, Abdominal; Aortic Aneurysm, Thoracic; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Disease Progression; Inflammation Mediators; Macrophages; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Sirtuin 1; Time Factors; Tumor Necrosis Factor-alpha
PubMed: 23535154
DOI: 10.1016/j.jtcvs.2013.02.073 -
Annals of Translational Medicine Oct 2021To investigate the protective effect of resolvin D1 (RvD1) on aortic dissection (AD) in mice and explore the related mechanisms.
BACKGROUND
To investigate the protective effect of resolvin D1 (RvD1) on aortic dissection (AD) in mice and explore the related mechanisms.
METHODS
Mice were randomly divided into a blank group, model group, and RvD1 group. The RvD1 and model groups were administered 0.4% β-aminopropionitrile (BAPN) solution, while the blank group was administered distilled water. When the experiment began, whether mice had AD was determined by echocardiogram. The RvD1 group was also administered RvD1 (30 µg/kg), while the model and blank groups were administered saline intraperitoneally. After 21 d, body weight trend and survival rate in the three groups were compared. The diameter of the ascending aorta of mice was detected by echocardiography. Then, the mice were sacrificed, and histopathological staining procedures were performed. Enzyme-linked immunosorbent assay (ELISA) was used to detect cytokines and chemokines in blood and tissue, respectively.
RESULTS
At 21 d, there was no statistically significant difference in body weight between three groups (P>0.05). The survival rate showed a significant difference between the RvD1 and model group (P<0.05). Echocardiography revealed that compared with the RvD1 and blank groups, aortic dilatation was significant in the model group. Pathological staining showed that the destruction of the aortic wall structure and inflammatory cell infiltration were more noticeable in the model group than in the RvD1 group. A slight disintegration of elastic fibers and collagen in the aorta was observed in the RvD1 group, and the aortic structure was clear. The results of ELISA showed that the inflammatory factors levels in the RvD1 group, although higher than those in blank group, were significantly decreased compared with the model group. The ELISA results of AD tissue showed that at 21 d, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels in the aorta were significantly decreased in the RvD1 group compared with the model group (P<0.05).
CONCLUSIONS
Administration of RvD1 significantly delayed aortic dilation and disintegration and inhibited local macrophage and neutrophil infiltration in the early stages of aortic injury. Moreover, RvD1 significantly downregulated the expression of cytokines and chemokines in aortic tissues and serum and improved aortic remodeling.
PubMed: 34805360
DOI: 10.21037/atm-21-3986 -
Frontiers in Cardiovascular Medicine 2021Numerous pieces of evidence have indicated that thoracic aortic dissection (TAD) is an inflammatory disease. Sphingosine-1-phosphate receptor 2 (S1PR2) signaling is a...
Numerous pieces of evidence have indicated that thoracic aortic dissection (TAD) is an inflammatory disease. Sphingosine-1-phosphate receptor 2 (S1PR2) signaling is a driver in multiple inflammatory diseases. Here, we examined the S1PR2 expression in TAD lesions and explored the effect of interfering with S1PR2 on TAD formation and progression. Aorta specimens and blood samples were collected from patients with TAD and matched controls. The expression of S1PR1, S1PR2, and S1PR3 was examined. The effect of inhibiting S1PR2 on TAD was evaluated in a TAD mouse model induced by β-aminopropionitrile fumarate (BAPN) and AngII. The presence of sphingosine kinase 1 (SPHK1), S1P, and neutrophil extracellular traps (NETs) was investigated. Further, the possible association between S1PR2 signaling and NETs in TAD was analyzed. In the aortic tissues of patients with TAD and a mouse model, the S1PR2 expression was significantly up-regulated. In the TAD mouse model, JTE013, a specific S1PR2 antagonist, not only blunted the TAD formation and aortic rupture, but also preserved the elastic fiber architecture, reduced the smooth muscle cells apoptosis level, and mitigated the aortic wall inflammation. Augmented tissue protein expression of SPHK1, citrullinated histone H3 (CitH3, a specific marker of NETs), and serum S1P, CitH3 were detected in TAD patients. Surgical repair normalized the serum S1P and CitH3 levels. Immunofluorescence staining revealed that S1PR2 colocalized with NETs. The protein expression levels of SPHK1 and serum S1P levels positively correlated with the protein expression and serum levels of CitH3, separately. Furthermore, JTE013 treatment reduced NETs accumulation. Inhibiting S1PR2 attenuates TAD formation and prevents aortic rupture. Targeting S1PR2 may provide a promising treatment strategy against TAD.
PubMed: 34977175
DOI: 10.3389/fcvm.2021.748486 -
International Journal of Molecular... Jan 2023Cystinosis is a rare, devastating hereditary disease secondary to recessive gene mutations. The most commonly used diagnostic method is confirmation of an elevated...
Cystinosis is a rare, devastating hereditary disease secondary to recessive gene mutations. The most commonly used diagnostic method is confirmation of an elevated leukocyte cystine level; however, this method is expensive and difficult to perform. This study aimed to identify candidate biomarkers for the diagnosis and follow-up of cystinosis based on multiomics studies. The study included three groups: newly-diagnosed cystinosis patients (patient group, n = 14); cystinosis patients under treatment (treatment group, n = 19); and healthy controls (control group, n = 30). Plasma metabolomics analysis identified 10 metabolites as candidate biomarkers that differed between the patient and control groups [L-serine, taurine, lyxose, 4-trimethylammoniobutanoic acid, orotic acid, glutathione, PE(O-18:1(9Z)/0:0), 2-hydroxyphenyl acetic acid, acetyl-N-formil-5-metoxikinuramine, 3-indoxyl sulphate]. As compared to the healthy control group, in the treatment group, hypotaurine, phosphatidylethanolamine, N-acetyl-d-mannosamine, 3-indolacetic acid, p-cresol, phenylethylamine, 5-aminovaleric acid, glycine, creatinine, and saccharic acid levels were significantly higher, and the metabolites quinic acid, capric acid, lenticin, xanthotoxin, glucose-6-phosphate, taurine, uric acid, glyceric acid, alpha-D-glucosamine phosphate, and serine levels were significantly lower. Urinary metabolomic analysis clearly differentiated the patient group from the control group by means of higher allo-inositol, talose, glucose, 2-hydroxybutiric acid, cystine, pyruvic acid, valine, and phenylalanine levels, and lower metabolite (N-acetyl-L-glutamic acid, 3-aminopropionitrile, ribitol, hydroquinone, glucuronic acid, 3-phosphoglycerate, xanthine, creatinine, and 5-aminovaleric acid) levels in the patient group. Urine metabolites were also found to be significantly different in the treatment group than in the control group. Thus, this study identified candidate biomarkers that could be used for the diagnosis and follow-up of cystinosis.
Topics: Humans; Cystinosis; Cystine; Creatinine; Biomarkers; Glutathione; Amino Acid Transport Systems, Neutral
PubMed: 36768921
DOI: 10.3390/ijms24032603 -
Translational Andrology and Urology May 2022The mechanisms of the microenergy acoustic pulse (MAP) therapy on restoring structure and function of pelvic floor muscles (PFM) after simulated birth injury are not...
BACKGROUND
The mechanisms of the microenergy acoustic pulse (MAP) therapy on restoring structure and function of pelvic floor muscles (PFM) after simulated birth injury are not well understood.
METHODS
A total 24 female Sprague-Dawley rats were randomly grouped into sham control (sham), vaginal balloon dilation and ovariectomy (VBDO), VBDO + β-aminopropionitrile (BAPN, an irreversible LOX inhibitor), and VBDO + BAPN and treated with MAP (n=6 in each group). The MAP therapy was administered 2 times per week for 4 weeks with 1-week washout, the functional and histological studies were conducted in all 24 rats. The viscoelastic behavior of the PFM, including iliococcygeus (IC) and pubococcygeus (PC), was examined with a biomechanical assay. The structure of the PFM was assessed by immunofluorescence and Masson's trichrome staining.
RESULTS
The leak point pressure (LPP) assay demonstrated that the MAP therapy group had higher LPPs compared to that of VBDO and BAPN groups. In the sham group, the muscular stiffness (K) of IC muscle was significantly higher than that of PC muscle while the pelvic floor muscle rebound activity (MRA) of PC muscle was stronger than that of IC muscle (291.26±45.33 and 241.18±14.23 N/cm, respectively). Both VBDO and BAPN decreased the MRA and increased the K in both IC and PC. Histologic examination revealed increased fibrous tissue (collagen) and degeneration of muscle fibers in both VBDO and BAPN groups. MAP therapy significantly reduced the collagen content and improved the architecture of muscle fibers.
CONCLUSIONS
MAP appears to restore the structure and function of PFM by regenerating muscular fibers and improving biomechanical properties in an animal model of simulated birth injury.
PubMed: 35693721
DOI: 10.21037/tau-22-30 -
Cells Oct 2022Aortic dissection (AD) is a lethal aortic pathology without effective medical treatments since the underlying pathological mechanisms responsible for AD remain elusive....
Aortic dissection (AD) is a lethal aortic pathology without effective medical treatments since the underlying pathological mechanisms responsible for AD remain elusive. Matrix metalloproteinase-8 (MMP8) has been previously identified as a key player in atherosclerosis and arterial remodeling. However, the functional role of MMP8 in AD remains largely unknown. Here, we report that an increased level of MMP8 was observed in 3-aminopropionitrile fumarate (BAPN)-induced murine AD. AD incidence and aortic elastin fragmentation were markedly reduced in MMP8-knockout mice. Importantly, pharmacologic inhibition of MMP8 significantly reduced the AD incidence and aortic elastin fragmentation. We observed less inflammatory cell accumulation, a lower level of aortic inflammation, and decreased smooth muscle cell (SMC) apoptosis in MMP8-knockout mice. In line with our previous observation that MMP8 cleaves Ang I to generate Ang II, BAPN-treated MMP8-knockout mice had increased levels of Ang I, but decreased levels of Ang II and lower blood pressure. Additionally, we observed a decreased expression level of vascular cell adhesion molecule-1 (VCAM1) and a reduced level of reactive oxygen species (ROS) in MMP8-knockout aortas. Mechanistically, our data show that the Ang II/VCAM1 signal axis is responsible for MMP8-mediated inflammatory cell invasion and transendothelial migration, while MMP8-mediated SMC inflammation and apoptosis are attributed to Ang II/ROS signaling. Finally, we observed higher levels of aortic and serum MMP8 in patients with AD. We therefore provide new insights into the molecular mechanisms underlying AD and identify MMP8 as a potential therapeutic target for this life-threatening aortic disease.
Topics: Animals; Mice; Aminopropionitrile; Aortic Dissection; Angiotensin II; Disease Models, Animal; Elastin; Inflammation; Matrix Metalloproteinase 8; Mice, Knockout; Reactive Oxygen Species; Vascular Cell Adhesion Molecule-1; Humans
PubMed: 36291087
DOI: 10.3390/cells11203218 -
European Journal of Vascular and... Dec 2020Thoracic aortic dissection (TAD) is associated with matrix changes, biochemical changes, and inflammatory markers like interleukin-1 beta (IL-1β). However, the exact...
OBJECTIVE
Thoracic aortic dissection (TAD) is associated with matrix changes, biochemical changes, and inflammatory markers like interleukin-1 beta (IL-1β). However, the exact mechanism remains unknown. This study aimed to investigate the role of IL-1β, matrix metalloproteinase (MMP)-2, MMP-9, smooth muscle cell apoptosis, and elastic fibre fracture in the development of TAD in a rat model.
METHODS
The TAD rat model was induced by β-aminopropionitrile (BAPN). TAD was investigated in 112 male Sprague-Dawley rats, which were equally divided into four groups of 28 rats (Control, BAPN, BAPN + IL-1β, and BAPN + IL-1β antibody). Systolic blood pressure, survival, and the development of TAD were measured after six weeks. Expression of IL-1β, MMP-2, and MMP-9 was measured by Western blot. Apoptosis, aortic elastin concentration, and biomechanical characteristics were measured by the TdT mediated dUTP nick end labelling assay, Victoria blue staining, and in vitro testing.
RESULTS
During six weeks, the mortality was 0% (0/28) in the control group, 53.6% (15/28) in the BAPN group (p < .001 compared with the control group), 75.0% (21/28) in the BAPN + IL-1β group (p = .007 compared with the BAPN group), and 35.7% (10/28) in the BAPN + IL-1β antibody group (p = .023 compared with BAPN group and p < .001 compared with the BAPN + IL-1β group). IL-1β treatment deteriorates BAPN induced mortality and aneurysm expansion, which were attenuated by anti-IL-1β treatment. In BAPN + IL-1β group, stress and strain parameters were decreased by 13.5%-53.5% and elastin content was decreased by 14%, and IL-1β, MMP-2, and MMP-9 were expressed higher by 117%, 108%, and 75% when compared with the rats in the BAPN group. Contrarily, in the BAPN + IL-1β antibody group, the above changes could be completely (strain, elastin content, and expression of MMP-2) or partly (elasticity modulus, stress, and expression of MMP-9) blocked by anti-IL-1β treatment.
CONCLUSION
IL-1β plays a critical role in TAD formation by altering the expression of MMP-2 and MMP-9, degrading the aortic wall matrix, causing elastic fibre rupture, and changing the stress or strain of the aortic wall. Anti-IL-1β reduces the later effects and could be one of the molecular targets for prognosis and drug treatment of TAD in the future.
Topics: Aminopropionitrile; Aortic Dissection; Animals; Antibodies; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Apoptosis; Disease Models, Animal; Elastin; Interleukin-1beta; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Rats; Rats, Sprague-Dawley; Survival Rate
PubMed: 33004280
DOI: 10.1016/j.ejvs.2020.08.032 -
International Journal of Biological... 2024Thoracic aortic dissection (TAD) is one of the cardiovascular diseases with high incidence and fatality rates. Vascular smooth muscle cells (VSMCs) play a vital role in...
Thoracic aortic dissection (TAD) is one of the cardiovascular diseases with high incidence and fatality rates. Vascular smooth muscle cells (VSMCs) play a vital role in TAD formation. Recent studies have shown that extracellular S100A4 may participate in VSMCs regulation. However, the mechanism(s) underlying this association remains elusive. Consequently, this study investigated the role of S100A4 in VSMCs regulation and TAD formation. Hub genes were screened based on the transcriptome data of aortic dissection in the Gene Expression Synthesis database. Three-week-old male S100A4 overexpression (AAV9- S100A4 OE) and S100A4 knockdown (AAV9- S100A4 KD) mice were exposed to β-aminopropionitrile monofumarate through drinking water for 28 days to create the murine TAD model. S100A4 was observed to be the hub gene in aortic dissection. Furthermore, overexpression of S100A4 was exacerbated, whereas inhibition of S100A4 significantly improved TAD progression. In the TAD model, the S100A4 was observed to aggravate the phenotypic transition of VSMCs. Additionally, lysyl oxidase (LOX) was an important target of S100A4 in TAD. S100A4 interacted with LOX in VSMCs, reduced mature LOX (m-LOX), and decreased elastic fiber deposition, thereby disrupting extracellular matrix homeostasis and promoting TAD development. Elastic fiber deposition in human aortic tissues was negatively correlated with the expression of S100A4, which in turn, was negatively correlated with LOX. Our data showed that S100A4 modulates TADprogression, induces lysosomal degradation of m-LOX, and reduces the deposition of elastic fibers by interacting with LOX, thus contributing to the disruption of extracellular matrix homeostasis in TAD. These findings suggest that S100A4 may be a new target for the prevention and treatment of TAD.
Topics: Male; Humans; Mice; Animals; Aortic Dissection; Aorta; Extracellular Matrix; Dissection, Thoracic Aorta; S100 Calcium-Binding Protein A4
PubMed: 38164183
DOI: 10.7150/ijbs.83091