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Scientific Reports Jun 2024There is no treatment for acute aortic dissection (AAD) targeting inflammatory cells. We aimed to identify the new therapeutic targets associated with inflammatory...
There is no treatment for acute aortic dissection (AAD) targeting inflammatory cells. We aimed to identify the new therapeutic targets associated with inflammatory cells. We characterized the specific distribution of myeloid cells of both human type A AAD samples and a murine AAD model generated using angiotensin II (ANGII) and β-aminopropionitrile (BAPN) by single-cell RNA sequencing (scRNA-seq). We also examined the effect of an anti-interleukin-1β (IL-1β) antibody in the murine AAD model. IL1B inflammatory macrophages and classical monocytes were increased in human AAD samples. Trajectory analysis demonstrated that IL1B inflammatory macrophages differentiated from S100A8/9/12 classical monocytes uniquely observed in the aorta of AAD. We found increased infiltration of neutrophils and monocytes with the expression of inflammatory cytokines in the aorta and accumulation of inflammatory macrophages before the onset of macroscopic AAD in the murine AAD model. In blocking experiments using an anti-IL-1β antibody, it improved survival of murine AAD model by preventing elastin degradation. We observed the accumulation of inflammatory macrophages expressing IL-1β in both human AAD samples and in a murine AAD model. Anti-IL-1β antibody could improve the mortality rate in mice, suggesting that it may be a treatment option for AAD.
Topics: Aortic Dissection; Interleukin-1beta; Animals; Humans; Macrophages; Mice; Disease Models, Animal; Male; Aminopropionitrile; Angiotensin II; Inflammation; Monocytes; Aorta; Mice, Inbred C57BL; Female
PubMed: 38937528
DOI: 10.1038/s41598-024-65931-3 -
Arteriosclerosis, Thrombosis, and... Jul 2024Most abdominal aortic aneurysms (AAAs) are small with low rupture risk (<1%/y) when diagnosed but slowly expand to ≥55 mm and undergo surgical repair. Patients and... (Review)
Review
CLINICAL PROBLEM
Most abdominal aortic aneurysms (AAAs) are small with low rupture risk (<1%/y) when diagnosed but slowly expand to ≥55 mm and undergo surgical repair. Patients and clinicians require medications to limit AAA growth and rupture, but drugs effective in animal models have not translated to patients.
RECOMMENDATIONS FOR INCREASING TRANSLATION FROM MOUSE MODELS
Use models that simulate human AAA tissue pathology, growth patterns, and rupture; focus on the clinically relevant outcomes of growth and rupture; design studies with the rigor required of human clinical trials; monitor AAA growth using reproducible ultrasound; and perform studies in both males and females.
SUMMARY OF STRENGTHS AND WEAKNESSES OF MOUSE MODELS
The aortic adventitial elastase oral β-aminopropionitrile model has many strengths including simulating human AAA pathology and modeling prolonged aneurysm growth. The Ang II (angiotensin II) model performed less well as it better simulates acute aortic syndrome than AAA. The elastase plus TGFβ (transforming growth factor-β) blocking antibody model displays a high rupture rate, making prolonged monitoring of AAA growth not feasible. The elastase perfusion and calcium chloride models both display limited AAA growth.
Topics: Animals; Aortic Aneurysm, Abdominal; Disease Models, Animal; Humans; Aortic Rupture; Pancreatic Elastase; Mice; Aorta, Abdominal; Female; Disease Progression; Male
PubMed: 38924435
DOI: 10.1161/ATVBAHA.124.320823 -
Acta Chimica Slovenica Apr 2024Many conformers of 3-aminopropionitrile are known. Due to the biomedical importance of 3-aminopropionitrile a full investigation of structural, vibrational, and other...
Many conformers of 3-aminopropionitrile are known. Due to the biomedical importance of 3-aminopropionitrile a full investigation of structural, vibrational, and other associated properties of all possible conformers was performed. The geometrical structures, relative stability, and vibrational frequencies of the gauche and trans 3-aminopropionitrile conformers have been studied using ab initio (CCSD/6-311+G(d,p)) and DFT (B3LYP and M06 functionals at 6-311+G(d,p) and aug-cc-pVDZ basis set) calculations. The conformational and vibrational studies of 3-aminopropionitrile molecule were presented here are in very good interpretation of the calculated data compared with very poor interpretation in previous studies. The results showed that the gauche 2 conformer is more stable by 0.19 kcal/mol than gauche 1, outlined as enthalpy change ΔH between the conformers, at CCSD/6-311+G(d,p). Additionally, the population analysis shows that the gauche conformers are more prevalent than the trans conformers in the gas phase, present at 72.8%, with gauche 2 being the dominating gauche conformer at 40.1%. These results are in good agreement with earlier experimental and theoretical conclusions. All minima conformers' thermodynamic characteristics have also been studied. The relevant bond lengths, bond angles, and dihedral angles were calculated at a different level of theory for all possible conformers. The geometrical outcomes of the conformers agree very well with the previous experimental results. Electrostatic potential surface (ESP) has been used to interpret the structure-activity relationship. The atomic charges are examined, together with the energy difference between HOMO (Highest Occupied Molecular Orbital) and LUMO (Lowest Unoccupied Molecular Orbital). Additionally, the HOMO-LUMO energy gap and other relevant molecular properties are computed. The most stable conformers' stabilization energy has been determined by the Natural Bond Orbital (NBO) analysis.
PubMed: 38919112
DOI: 10.17344/acsi.2023.8486 -
Food and Chemical Toxicology : An... Jun 2024Aortic dissection (AD) is a prevalent and acute clinical catastrophe characterized by abrupt manifestation, swift progression, and elevated fatality rates. Despite...
OBJECTIVE
Aortic dissection (AD) is a prevalent and acute clinical catastrophe characterized by abrupt manifestation, swift progression, and elevated fatality rates. Despite smoking being a significant risk factor for AD, the precise pathological process remains elusive. This investigation endeavors to explore the mechanisms by which smoking accelerates AD through ferroptosis induction.
METHODOLOGY
In this novel study, we detected considerable endothelial cell death by ferroptosis within the aortic inner lining of both human AD patients with a smoking history and murine AD models induced by β-aminopropionitrile, angiotensin II, and nicotine. Utilizing bioinformatic approaches, we identified microRNAs regulating the expression of the ferroptosis inhibitor Glutathione peroxidase 4 (GPX4). Nicotine's impact on ferroptosis was further assessed in human umbilical vein endothelial cells (HUVECs) through modulation of miR-1909-5p. Additionally, the therapeutic potential of miR-1909-5p antagomir was evaluated in vivo in nicotine-exposed AD mice.
FINDINGS
Our results indicate a predominance of ferroptosis over apoptosis, pyroptosis, and necroptosis in the aortas of AD patients who smoke. Nicotine exposure instigated ferroptosis in HUVECs, where the miR-1909-5p/GPX4 axis was implicated. Modulation of miR-1909-5p in these cells revealed its regulatory role over GPX4 levels and subsequent endothelial ferroptosis. In vivo, miR-1909-5p suppression reduced ferroptosis and mitigated AD progression in the murine model.
CONCLUSIONS
Our data underscore the involvement of the miR-1909-5p/GPX4 axis in the pathogenesis of nicotine-induced endothelial ferroptosis in AD.
PubMed: 38897284
DOI: 10.1016/j.fct.2024.114826 -
Autophagy Jul 2024Thoracic aortic dissection (TAD) is a severe disease, characterized by numerous apoptotic vascular smooth muscle cells (VSMCs). EDIL3/Del-1 is a secreted protein...
Thoracic aortic dissection (TAD) is a severe disease, characterized by numerous apoptotic vascular smooth muscle cells (VSMCs). EDIL3/Del-1 is a secreted protein involved in macrophage efferocytosis in acute inflammation. Here, we aimed to investigate whether EDIL3 promoted the internalization and degradation of apoptotic VSMCs during TAD. The levels of EDIL3 were decreased in the serum and aortic tissue from TAD mice. Global knockout () mice and bone marrow chimeric mice exhibited a considerable exacerbation in β-aminopropionitrile monofumarate (BAPN)-induced TAD, accompanied with increased apoptotic VSMCs accumulating in the damaged aortic tissue. Two types of phagocytes, RAW264.7 cells and bone marrow-derived macrophages (BMDMs) were used for in vitro efferocytosis assay. -deficient phagocytes exhibited inefficient internalization and degradation of apoptotic VSMCs. Instead, EDIL3 promoted the internalization phase through interacting with phosphatidylserine (PtdSer) on apoptotic VSMCs and binding to the macrophage ITGAV/α-ITGB3/β integrin. In addition, EDIL3 accelerated the degradation phase through activating LC3-associated phagocytosis (LAP). Mechanically, following the engulfment, EDIL3 enhanced the activity of SMPD1/acid sphingomyelinase in the phagosome through blocking ITGAV-ITGB3 integrin, which facilitates phagosomal reactive oxygen species (ROS) production by NAPDH oxidase CYBB/NOX2. Furthermore, exogenous EDIL3 supplementation alleviated BAPN-induced TAD and promoted apoptotic cell clearance. EDIL3 may be a novel factor for the prevention and treatment of TAD. BAPN: β-aminopropionitrile monofumarate; BMDM: bone marrow-derived macrophage; C12FDG: 5-dodecanoylaminofluorescein-di-β-D-galactopyranoside; CTRL: control; CYBB/NOX2: cytochrome b-245, beta polypeptide; DCFH-DA: 2',7'-dichlorofluorescin diacetate; EDIL3/Del-1: EGF-like repeats and discoidin I-like domains 3; EdU: 5-ethynyl-2'-deoxyuridine; EVG: elastic van Gieson; H&E: hematoxylin and eosin; IL: interleukin; LAP: LC3-associated phagocytosis; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; NAC: N-acetylcysteine; PtdSer: phosphatidylserine; rEDIL3: recombinant EDIL3; ROS: reactive oxygen species; SMPD1: sphingomyelin phosphodiesterase 1; TAD: thoracic aortic dissection; TEM: transmission electron microscopy; VSMC: vascular smooth muscle cell; WT: wild-type.
PubMed: 38873925
DOI: 10.1080/15548627.2024.2367191 -
Antioxidants (Basel, Switzerland) Apr 2024Lysyl oxidase (LOX)-mediated extracellular matrix crosslinking modulates calcification in atherosclerosis and aortic valve disease; however, this enzyme also induces...
Lysyl oxidase (LOX)-mediated extracellular matrix crosslinking modulates calcification in atherosclerosis and aortic valve disease; however, this enzyme also induces oxidative stress. We addressed the contribution of LOX-dependent oxidative stress to cardiovascular calcification. LOX is upregulated in human-calcified atherosclerotic lesions and atheromas from atherosclerosis-challenged LOX transgenic mice (TgLOX) and colocalized with a marker of oxidative stress (8-oxo-deoxyguanosine) in vascular smooth muscle cells (VSMCs). Similarly, in calcific aortic valves, high LOX expression was detected in valvular interstitial cells (VICs) positive for 8-oxo-deoxyguanosine, while LOX and LOXL2 expression correlated with osteogenic markers (SPP1 and RUNX2) and NOX2. In human VICs, mito-TEMPO and TEMPOL attenuated the increase in superoxide anion levels and the mineralization induced by osteogenic media (OM). Likewise, in OM-exposed VICs, β-aminopropionitrile (a LOX inhibitor) ameliorated both oxidative stress and calcification. Gain- and loss-of-function approaches in VICs demonstrated that while LOX silencing negatively modulates oxidative stress and calcification induced by OM, lentiviral LOX overexpression exacerbated oxidative stress and VIC calcification, effects that were prevented by mito-TEMPO, TEMPOL, and β-aminopropionitrile. Our data indicate that LOX-induced oxidative stress participates in the procalcifying effects of LOX activity in ectopic cardiovascular calcification, and highlight the multifaceted role played by LOX isoenzymes in cardiovascular diseases.
PubMed: 38790628
DOI: 10.3390/antiox13050523 -
Arteriosclerosis, Thrombosis, and... Jul 2024β-aminopropionitrile (BAPN) is a pharmacological inhibitor of LOX (lysyl oxidase) and LOXLs (LOX-like proteins). Administration of BAPN promotes aortopathies, although...
BACKGROUND
β-aminopropionitrile (BAPN) is a pharmacological inhibitor of LOX (lysyl oxidase) and LOXLs (LOX-like proteins). Administration of BAPN promotes aortopathies, although there is a paucity of data on experimental conditions to generate pathology. The objective of this study was to define experimental parameters and determine whether equivalent or variable aortopathies were generated throughout the aortic tree during BAPN administration in mice.
METHODS
BAPN was administered in drinking water for a period ranging from 1 to 12 weeks. The impacts of BAPN were first assessed with regard to BAPN dose, and mouse strain, age, and sex. BAPN-induced aortic pathological characterization was conducted using histology and immunostaining. To investigate the mechanistic basis of regional heterogeneity, the ascending and descending thoracic aortas were harvested after 1 week of BAPN administration before the appearance of overt pathology.
RESULTS
BAPN-induced aortic rupture predominantly occurred or originated in the descending thoracic aorta in young C57BL/6J or N mice. No apparent differences were found between male and female mice. For mice surviving 12 weeks of BAPN administration, profound dilatation was consistently observed in the ascending region, while there were more heterogeneous changes in the descending thoracic region. Pathological features were distinct between the ascending and descending thoracic regions. Aortic pathology in the ascending region was characterized by luminal dilatation and elastic fiber disruption throughout the media. The descending thoracic region frequently had dissections with false lumen formation, collagen deposition, and remodeling of the wall surrounding the false lumen. Cells surrounding the false lumen were predominantly positive for α-SMA (α-smooth muscle actin). One week of BAPN administration compromised contractile properties in both regions equivalently, and RNA sequencing did not show obvious differences between the 2 aortic regions in smooth muscle cell markers, cell proliferation markers, and extracellular components.
CONCLUSIONS
BAPN-induced pathologies show distinct, heterogeneous features within and between ascending and descending aortic regions in mice.
Topics: Animals; Aminopropionitrile; Aorta, Thoracic; Female; Male; Mice, Inbred C57BL; Disease Models, Animal; Aortic Rupture; Mice; Vascular Remodeling; Dilatation, Pathologic; Muscle, Smooth, Vascular; Age Factors; Time Factors; Sex Factors; Cell Proliferation; Protein-Lysine 6-Oxidase
PubMed: 38779856
DOI: 10.1161/ATVBAHA.123.320402 -
FASEB Journal : Official Publication of... May 2024Inflammation assumes a pivotal role in the aortic remodeling of aortic dissection (AD). Asiatic acid (AA), a triterpene compound, is recognized for its strong...
Inflammation assumes a pivotal role in the aortic remodeling of aortic dissection (AD). Asiatic acid (AA), a triterpene compound, is recognized for its strong anti-inflammatory properties. Yet, its effects on β-aminopropionitrile (BAPN)-triggered AD have not been clearly established. The objective is to determine whether AA attenuates adverse aortic remodeling in BAPN-induced AD and clarify potential molecular mechanisms. In vitro studies, RAW264.7 cells pretreated with AA were challenged with lipopolysaccharide (LPS), and then the vascular smooth muscle cells (VSMCs)-macrophage coculture system was established to explore intercellular interactions. To induce AD, male C57BL/6J mice at three weeks of age were administered BAPN at a dosage of 1 g/kg/d for four weeks. To decipher the mechanism underlying the effects of AA, RNA sequencing analysis was conducted, with subsequent validation of these pathways through cellular experiments. AA exhibited significant suppression of M1 macrophage polarization. In the cell coculture system, AA facilitated the transformation of VSMCs into a contractile phenotype. In the mouse model of AD, AA strikingly prevented the BAPN-induced increases in inflammation cell infiltration and extracellular matrix degradation. Mechanistically, RNA sequencing analysis revealed a substantial upregulation of CX3CL1 expression in BAPN group but downregulation in AA-treated group. Additionally, it was observed that the upregulation of CX3CL1 negated the beneficial impact of AA on the polarization of macrophages and the phenotypic transformation of VSMCs. Crucially, our findings revealed that AA is capable of downregulating CX3CL1 expression, accomplishing this by obstructing the nuclear translocation of NF-κB p65. The findings indicate that AA holds promise as a prospective treatment for adverse aortic remodeling by suppressing the activity of NF-κB p65/CX3CL1 signaling pathway.
Topics: Animals; Mice; Male; Aortic Dissection; Pentacyclic Triterpenes; Vascular Remodeling; Mice, Inbred C57BL; RAW 264.7 Cells; Signal Transduction; Transcription Factor RelA; Chemokine CX3CL1; Muscle, Smooth, Vascular; Aminopropionitrile; Macrophages; Myocytes, Smooth Muscle
PubMed: 38703043
DOI: 10.1096/fj.202302327R -
The Journal of Biological Chemistry May 2024Thoracic aortic dissection (TAD) is a highly dangerous cardiovascular disorder caused by weakening of the aortic wall, resulting in a sudden tear of the internal face....
Thoracic aortic dissection (TAD) is a highly dangerous cardiovascular disorder caused by weakening of the aortic wall, resulting in a sudden tear of the internal face. Progressive loss of the contractile apparatus in vascular smooth muscle cells (VSMCs) is a major event in TAD. Exploring the endogenous regulators essential for the contractile phenotype of VSMCs may aid the development of strategies to prevent TAD. Krüppel-like factor 15 (KLF15) overexpression was reported to inhibit TAD formation; however, the mechanisms by which KLF15 prevents TAD formation and whether KLF15 regulates the contractile phenotype of VSMCs in TAD are not well understood. Therefore, we investigated these unknown aspects of KLF15 function. We found that KLF15 expression was reduced in human TAD samples and β-aminopropionitrile monofumarate-induced TAD mouse model. Klf15KO mice are susceptible to both β-aminopropionitrile monofumarate- and angiotensin II-induced TAD. KLF15 deficiency results in reduced VSMC contractility and exacerbated vascular inflammation and extracellular matrix degradation. Mechanistically, KLF15 interacts with myocardin-related transcription factor B (MRTFB), a potent serum response factor coactivator that drives contractile gene expression. KLF15 silencing represses the MRTFB-induced activation of contractile genes in VSMCs. Thus, KLF15 cooperates with MRTFB to promote the expression of contractile genes in VSMCs, and its dysfunction may exacerbate TAD. These findings indicate that KLF15 may be a novel therapeutic target for the treatment of TAD.
Topics: Animals; Humans; Male; Mice; Angiotensin II; Aortic Aneurysm, Thoracic; Dissection, Thoracic Aorta; Kruppel-Like Transcription Factors; Mice, Inbred C57BL; Mice, Knockout; Muscle Contraction; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenotype; Transcription Factors
PubMed: 38582447
DOI: 10.1016/j.jbc.2024.107260 -
The American Journal of Pathology Jul 2024Two major constituents of exfoliation material, fibrillin-1 and lysyl oxidase-like 1 (encoded by FBN1 and LOXL1), are implicated in exfoliation glaucoma, yet their...
Two major constituents of exfoliation material, fibrillin-1 and lysyl oxidase-like 1 (encoded by FBN1 and LOXL1), are implicated in exfoliation glaucoma, yet their individual contributions to ocular phenotype are minor. To test the hypothesis that a combination of FBN1 mutation and LOXL1 deficiency exacerbates ocular phenotypes, the pan-lysyl oxidase inhibitor β-aminopropionitrile (BAPN) was used to treat adult wild-type (WT) mice and mice heterozygous for a missense mutation in Fbn1 (Fbn1) for 8 weeks and their eyes were examined. Although intraocular pressure did not change and exfoliation material was not detected in the eyes, BAPN treatment worsened optic nerve and axon expansion in Fbn1 mice, an early sign of axonal damage in rodent models of glaucoma. Disruption of elastic fibers was detected only in Fbn1 mice, which increased with BAPN treatment, as shown by histologic and immunohistochemical staining of the optic nerve pia mater. Transmission electron microscopy showed that Fbn1 mice had fewer microfibrils, smaller elastin cores, and a lower density of elastic fibers compared with WT mice in control groups. BAPN treatment led to elastin core expansion in both WT and Fbn1 mice, but an increase in the density of elastic fiber was confined to Fbn1 mice. LOX inhibition had a stronger effect on optic nerve and elastic fiber parameters in the context of Fbn1 mutation, indicating the Marfan mouse model with LOX inhibition warrants further investigation for exfoliation glaucoma pathogenesis.
Topics: Animals; Protein-Lysine 6-Oxidase; Marfan Syndrome; Disease Models, Animal; Mice; Fibrillin-1; Aminopropionitrile; Optic Nerve; Elastic Tissue; Intraocular Pressure; Fibrillins; Mice, Inbred C57BL; Amino Acid Oxidoreductases; Glaucoma; Microfilament Proteins; Adipokines
PubMed: 38548269
DOI: 10.1016/j.ajpath.2024.03.002