scholarly journals Circular RNA RBM33 contributes to extracellular matrix degradation via miR-4268/EPHB2 axis in abdominal aortic aneurysm

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e12232
Author(s):  
Shizhi Wang ◽  
Qingwen Yuan ◽  
Wenpeng Zhao ◽  
Weimin Zhou
Keyword(s):  
Extracellular Matrix ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Matrix Metalloproteinase 2 ◽  
Luciferase Reporter ◽  
Circular Rnas ◽  
Ang Ii ◽  
Abdominal Aortic ◽  
Gene Assay ◽  
Ecm Degradation

Background Abdominal aortic aneurysm (AAA) is a complex vascular disease involving expansion of the abdominal aorta. Extracellular matrix (ECM) degradation is crucial to AAA pathogenesis, however, the specific molecular mechanism remains unclear. This study aimed to investigate differentially expressed circular RNAs (DEcircRNAs) involved in ECM degradation of AAA. Methods Transcriptome sequencing was used to analyze the DEcircRNAs between the AAA tissues and normal tissues. The expression of circRNAs in tissues and cells was validated using quantitative reverse transcription PCR (RT-qPCR). Overexpression of circRNAs in vascular smooth muscle cells (VSMCs) treated with angiotensin II (Ang II) was employed to explore its effect on ECM degradation of AAA. Bioinformatic technology, luciferase reporter gene assay, RT-qPCR, and rescue experiment were employed to evaluate the regulatory mechanism of circRNA. Results We identified 65 DEcircRNAs in AAA tissues compared with normal abdominal aortic tissues, including 30 up-regulated and 35 down-regulated circRNAs, which were mainly involved in inflammation and ECM-related functions and pathways. Moreover, circRBM33 was significantly increased in AAA tissues and Ang II-induced VSMCs compared with control samples. Overexpression of circRBM33 increased the expression of ECM-related molecule matrix metalloproteinase-2 and reduced the tissue inhibitor of matrix metalloproteinases-1 expression. Mechanistically, miR-4268 targeted binding to circRBM33 and inhibited the luciferase activity of circRBM33. Overexpression of circRBM33 induced the expression of EPH receptor B2 (EPHB2), and this effect was countered by miR-4268 mimics. Conclusions Overall, our data suggest that circRBM33 might be involved in AAA progression by regulating ECM degradation via the miR-4268/EPHB2 axis.

scholarly journals Inducible Depletion of Calpain-2 Mitigates Abdominal Aortic Aneurysm in Mice

2021 ◽  
Author(s):  
Latha Muniappan ◽  
Michihiro Okuyama ◽  
Aida Javidan ◽  
Devi Thiagarajan ◽  
Weihua Jiang ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Structural Integrity ◽  
Mesenchymal Cell ◽  
Ang Ii ◽  
Structural Protein ◽  
Abdominal Aortic ◽  
Calpain 2

Objective: Cytoskeletal structural proteins maintain cell structural integrity by bridging extracellular matrix with contractile filaments. During abdominal aortic aneurysm (AAA) development, (1) aortic medial degeneration is associated with loss of smooth muscle cell integrity and (2) fibrogenic mesenchymal cells mediate extracellular matrix remodeling. Calpains cleave cytoskeletal proteins that maintain cell structural integrity. Pharmacological inhibition of calpains exert beneficial effects on Ang II (angiotensin II)–induced AAAs in LDLR −/− (low-density receptor deficient) mice. Here, we evaluated the functional contribution of fibrogenic mesenchymal cells-derived calpain-2 on (1) cytoskeletal structural protein and extracellular matrix alterations and (2) AAA progression. Approach and Results: Calpain-2 protein and cytoskeletal protein (filamin and talin) fragmentation are significantly elevated in human and Ang II–induced AAAs in mice. To examine the relative contribution of calpain-2 in AAA development, calpain-2 floxed mice in an LDLr −/− background were bred to mice with a tamoxifen-inducible form of Cre under control of either the ubiquitous promoter, chicken β-actin, or fibrogenic mesenchymal cell-specific promoter, Col1α2. Ubiquitous or fibrogenic mesenchymal cell-specific depletion of calpain-2 in mice suppressed Ang II–induced AAAs, filamin/talin fragmentation, while promoting extracellular matrix protein, collagen in the aortas. Calpain-2 silencing in aortic smooth muscle cells or fibroblasts reduced Ang II–induced filamin fragmentation. In addition, silencing of filamin in aortic SMCs significantly reduced collagen protein. Furthermore, calpain-2 deficiency suppressed rupture of established Ang II–induced AAAs in mice. Conclusions: Our studies implicate that calpain-2 deficiency prevents (1) Ang II–induced cytoskeletal structural protein fragmentation and AAA development and (2) stabilize and suppress rupture of established AAAs in mice.

scholarly journals Targeting Tyrosine Hydroxylase for Abdominal Aortic Aneurysm: Impact on Inflammation, Oxidative Stress, and Vascular Remodeling

Hypertension ◽  
2021 ◽  
Author(s):  
Laia Cañes ◽  
Judith Alonso ◽  
Carme Ballester-Servera ◽  
Saray Varona ◽  
José R. Escudero ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Abdominal Aortic Aneurysm ◽  
Tyrosine Hydroxylase ◽  
Aortic Aneurysm ◽  
Specific Inhibitor ◽  
Orphan Receptor ◽  
Matrix Metalloproteinase 2 ◽  
Ang Ii ◽  
Abdominal Aortic ◽  
The Impact

Pharmacological treatments for preventing abdominal aortic aneurysm (AAA) rupture or slowing aneurysm progression remain a challenge. It is increasingly recognized that sympathetic activity might play a role in the pathogenesis of AAA; however, the impact of this pathway remains unclear. Here, we show that the expression of tyrosine hydroxylase ( TH ), dopamine β-hydroxylase ( DBH ), and the norepinephrine transporter SLC6A2 is upregulated in abdominal aorta samples from AAA patients and in the aneurysmal aorta from 2 animal models susceptible to Ang II (angiotensin II)–induced AAA: the apolipoprotein E-deficient (ApoE −/− ) model and a transgenic mouse that overexpresses the human nuclear receptor NOR-1 (neuron-derived orphan receptor-1) in the vascular wall (TgNOR-1 VSMC ). TH localizes to sympathetic nerves innervating the local vasculature, but also to inflammatory cells, and scattered vascular smooth muscle cell in human and mouse AAA. Interestingly, the preventive effect of doxycycline on AAA formation in Ang II–treated TgNOR-1 VSMC mice was associated to the normalization of vascular Th expression. Moreover, the TH specific inhibitor α-methyl- p -tyrosine protected against Ang II–induced AAA formation, limiting the progressive increase in aortic diameter without affecting blood pressure. The drug normalized MMP2 (matrix metalloproteinase 2) expression and MMP activity, preserving elastin integrity, attenuated the Ang II–mediated rise in vascular oxidative stress and inflammatory markers and reduced the inflammatory infiltrate. Finally, NOR-1, whose expression correlated with that of TH in human AAA, was able to drive human TH transcriptional activity in transient transfection assays. Therefore, the upregulation of the TH pathway could be critical in the pathophysiology of AAA, supporting the potential of pharmacological strategies targeting TH for AAA management.

scholarly journals LncRNA SENCR suppresses abdominal aortic aneurysm formation by inhibiting smooth muscle cells apoptosis and extracellular matrix degradation

2020 ◽  
Author(s):  
Zhou Cai ◽  
Jianhua Huang ◽  
Junxiao Yang ◽  
Baihong Pan ◽  
Wei Wang ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Smooth Muscle Cells ◽  
Cell Apoptosis ◽  
Ang Ii ◽  
Matrix Degradation ◽  
Extracellular Matrix Degradation ◽  
Abdominal Aortic

Abdominal aortic aneurysm (AAA) is a progressive chronic dilatation of the abdominal aorta without effective medical treatment. This study aims to clarify the potential of long non-coding RNA SENCR as a treatment target in AAA. Angiotensin II (Ang-II) was used to establish AAA mouse model as well as a cell model based on the mouse aortic vascular smooth muscle cells (VSMCs). Reverse transcription quantitative PCR and western blot were performed to measure the expression of SENCR and proteins, respectively. Apoptotic rate in VSMCs was determined using Annexin V-FITC/PI double staining, and cell apoptosis in aortic tissues was determined by TUNEL staining. Hematoxylin and eosin and Elastica van Gieson staining were used for histological analysis of aortic tissues. SENCR was downregulated in AAA tissues and Ang-II-stimulated VSMCs. Overexpression of SENCR inhibited Ang-II-induced VSMC apoptosis, while inhibition of SENCR facilitated VSMC apoptosis. Moreover, overexpression of SENCR suppressed matrix metalloproteinase (MMP)-2 and MMP-9 expression and promoted tissue inhibitor of metalloproteinases 1 (TIMP-1) expression in Ang-II-induced VSMCs, while inhibition of SENCR expression led to the opposite results. In vivo, overexpressed SENCR improved the pathological change in aortic tissues and the damage in arterial wall elastic fibres induced by Ang-II, as well as it suppressed Ang-II-induced cell apoptosis and extracellular matrix degradation in aortic tissues. Overall, overexpression of SENCR inhibited AAA formation via suppressing VSMC apoptosis and extracellular matrix degradation. We provided a reliable evidence for SENCR acting as a potential target for AAA treatment.

scholarly journals IKK Epsilon Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice by Inhibiting Inflammation, Oxidative Stress, and Apoptosis

2020 ◽  
Vol 2020 ◽  
pp. 1-16
Author(s):  
Hao Chai ◽  
ZhongHao Tao ◽  
YongChao Qi ◽  
HaoYu Qi ◽  
Wen Chen ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Ang Ii ◽  
Elastin Degradation ◽  
Maximal Diameter ◽  
Abdominal Aortic ◽  
Primary Mouse

Abdominal aortic aneurysm (AAA) is a vascular disorder that is considered a chronic inflammatory disease. However, the precise molecular mechanisms involved in AAA have not been fully elucidated. Recently, significant progress has been made in understanding the function and mechanism of action of inhibitor of kappa B kinase epsilon (IKKε) in inflammatory and metabolic diseases. The angiotensin II- (Ang II-) induced or pharmacological inhibitors were established to test the effects of IKKε on AAA in vivo. After mice were continuously stimulated with Ang II for 28 days, morphologically, we found that knockout of IKKε reduced AAA formation and drastically reduced maximal diameter and severity. We also observed a decrease in elastin degradation and medial destruction, which were independent of systolic blood pressure or plasma cholesterol concentrations. Western blot analyses and immunohistochemical staining were carried out to measure IKKε expression in AAA tissues and cell lines. AAA phenotype of mice was measured by ultrasound and biochemical indexes. In zymography, immunohistology staining, immunofluorescence staining, and reactive oxygen species (ROS) analysis, TUNEL assay was used to examine the effects of IKKε on AAA progression in AAA mice. IKKε deficiency significantly inhibited inflammatory macrophage infiltration, matrix metalloproteinase (MMP) activity, ROS production, and vascular smooth muscle cell (VSMC) apoptosis. We used primary mouse aortic VSMC isolated from apolipoprotein E (Apoe) −/− and Apoe−/−IKKε−/− mice. Mechanistically, IKKε deficiency blunted the activation of the ERK1/2 pathway. The IKKε inhibitor, amlexanox, has the same impact in AAA. Our results demonstrate a critical role of IKKε in AAA formation induced by Ang II in Apoe−/− mice. Targeting IKKε may constitute a novel therapeutic strategy to prevent AAA progression.

scholarly journals Excessive EP4 Signaling in Smooth Muscle Cells Induces Abdominal Aortic Aneurysm by Amplifying Inflammation

2020 ◽  
Vol 40 (6) ◽  
pp. 1559-1573
Author(s):  
Taro Hiromi ◽  
Utako Yokoyama ◽  
Daisuke Kurotaki ◽  
Al Mamun ◽  
Ryo Ishiwata ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Macrophage Infiltration ◽  
Prostaglandin E ◽  
Ang Ii ◽  
Inflammatory Monocyte ◽  
Abdominal Aortic

Objective: Excessive prostaglandin E 2 production is a hallmark of abdominal aortic aneurysm (AAA). Enhanced expression of prostaglandin E 2 receptor EP4 (prostaglandin E receptor 4) in vascular smooth muscle cells (VSMCs) has been demonstrated in human AAAs. Although moderate expression of EP4 contributes to vascular homeostasis, the roles of excessive EP4 in vascular pathology remain uncertain. We aimed to investigate whether EP4 overexpression in VSMCs exacerbates AAAs. Approach and Results: We constructed mice with EP4 overexpressed selectively in VSMCs under an SM22α promoter (EP4-Tg). Most EP4-Tg mice died within 2 weeks of Ang II (angiotensin II) infusion due to AAA, while nontransgenic mice given Ang II displayed no overt phenotype. EP4-Tg developed much larger AAAs than nontransgenic mice after periaortic CaCl 2 application. In contrast, EP4 fl/+ ;SM22-Cre;ApoE −/ − and EP4 fl/+ ;SM22-Cre mice, which are EP4 heterozygous knockout in VSMCs, rarely exhibited AAA after Ang II or CaCl 2 treatment, respectively. In Ang II–infused EP4-Tg aorta, Ly6C hi inflammatory monocyte/macrophage infiltration and MMP-9 (matrix metalloprotease-9) activation were enhanced. An unbiased analysis revealed that EP4 stimulation positively regulated the genes binding cytokine receptors in VSMCs, in which IL (interleukin)-6 was the most strongly upregulated. In VSMCs of EP4-Tg and human AAAs, EP4 stimulation caused marked IL-6 production via TAK1 (transforming growth factor-β–activated kinase 1), NF-κB (nuclear factor-kappa B), JNK (c-Jun N-terminal kinase), and p38. Inhibition of IL-6 prevented Ang II–induced AAA formation in EP4-Tg. In addition, EP4 stimulation decreased elastin/collagen cross-linking protein LOX (lysyl oxidase) in both human and mouse VSMCs. Conclusions: Dysregulated EP4 overexpression in VSMCs promotes inflammatory monocyte/macrophage infiltration and attenuates elastin/collagen fiber formation, leading to AAA exacerbation.

scholarly journals Suppression of abdominal aortic aneurysm formation by inhibition of prolyl hydroxylase domain protein through attenuation of inflammation and extracellular matrix disruption

2014 ◽  
Vol 126 (9) ◽  
pp. 671-678 ◽  
Author(s):  
Aya Watanabe ◽  
Toshihiro Ichiki ◽  
Chikahiro Sankoda ◽  
Yusuke Takahara ◽  
Jiro Ikeda ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Cobalt Chloride ◽  
Prolyl Hydroxylase ◽  
Abdominal Aneurysm ◽  
Aneurysm Formation ◽  
Abdominal Aortic ◽  
Domain Protein ◽  
Prolyl Hydroxylase Domain

Inhibition of prolyl hydroxylase domain protein by cobalt chloride suppressed calcium chloride-induced abdominal aneurysm formation in mice.

scholarly journals Deficiency of peroxiredoxin 2 exacerbates angiotensin II-induced abdominal aortic aneurysm

2020 ◽  
Vol 52 (9) ◽  
pp. 1587-1601
Author(s):  
Se-Jin Jeong ◽  
Min Ji Cho ◽  
Na Young Ko ◽  
Sinai Kim ◽  
In-Hyuk Jung ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Negative Regulator ◽  
Aortic Dilatation ◽  
Ang Ii ◽  
Peroxiredoxin 2 ◽  
Structural Deterioration ◽  
Abdominal Aortic

Abstract Abdominal aortic aneurysm (AAA) is an inflammatory vascular disease characterized by structural deterioration of the aorta caused by inflammation and oxidative stress, leading to aortic dilatation and rupture. Peroxiredoxin 2 (PRDX2), an antioxidant enzyme, has been reported as a potential negative regulator of inflammatory vascular diseases, and it has been identified as a protein that is increased in patients with ruptured AAA compared to patients with nonruptured AAA. In this study, we demonstrated that PRDX2 was a pivotal factor involved in the inhibition of AAA progression. PRDX2 levels were increased in AAA compared with those in normal aortas in both humans and mice. Ultrasound imaging revealed that the loss of PRDX2 accelerated the development of AAA in the early stages and increased AAA incidence in mice infused with angiotensin II (Ang II). Prdx2−/− mice infused with Ang II exhibited increased aortic dilatation and maximal aortic diameter without a change in blood pressure. Structural deterioration of the aortas from Prdx2−/− mice infused with Ang II was associated with increases in the degradation of elastin, oxidative stress, and intramural thrombi caused by microhemorrhages, immature neovessels, and the activation of matrix metalloproteinases compared to that observed in controls. Moreover, an increase in inflammatory responses, including the production of cell adhesion molecules and the accumulation of inflammatory cells and proinflammatory cytokines due to PRDX2 deficiency, accelerated Ang II-induced AAA progression. Our data confirm that PRDX2 plays a role as a negative regulator of the pathological process of AAA and suggest that increasing PRDX2 activity may be a novel strategy for the prevention and treatment of AAA.

scholarly journals Apelin protects against abdominal aortic aneurysm and the therapeutic role of neutral endopeptidase resistant apelin analogs

2019 ◽  
Vol 116 (26) ◽  
pp. 13006-13015 ◽  
Author(s):  
Wang Wang ◽  
Mengcheng Shen ◽  
Conrad Fischer ◽  
Ratnadeep Basu ◽  
Saugata Hazra ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Aortic Rupture ◽  
Critical Role ◽  
Neutral Endopeptidase ◽  
Negative Regulator ◽  
Ang Ii ◽  
Direct Role ◽  
Abdominal Aortic

Abdominal aortic aneurysm (AAA) remains the second most frequent vascular disease with high mortality but has no approved medical therapy. We investigated the direct role of apelin (APLN) in AAA and identified a unique approach to enhance APLN action as a therapeutic intervention for this disease. Loss of APLN potentiated angiotensin II (Ang II)-induced AAA formation, aortic rupture, and reduced survival. Formation of AAA was driven by increased smooth muscle cell (SMC) apoptosis and oxidative stress inApln−/yaorta and in APLN-deficient cultured murine and human aortic SMCs. Ang II-induced myogenic response and hypertension were greater inApln−/ymice, however, an equivalent hypertension induced by phenylephrine, an α-adrenergic agonist, did not cause AAA or rupture inApln−/ymice. We further identified Ang converting enzyme 2 (ACE2), the major negative regulator of the renin-Ang system (RAS), as an important target of APLN action in the vasculature. Using a combination of genetic, pharmacological, and modeling approaches, we identified neutral endopeptidase (NEP) that is up-regulated in human AAA tissue as a major enzyme that metabolizes and inactivates APLN-17 peptide. We designed and synthesized a potent APLN-17 analog, APLN-NMeLeu9-A2, that is resistant to NEP cleavage. This stable APLN analog ameliorated Ang II-mediated adverse aortic remodeling and AAA formation in an established model of AAA, high-fat diet (HFD) inLdlr−/−mice. Our findings define a critical role of APLN in AAA formation through induction of ACE2 and protection of vascular SMCs, whereas stable APLN analogs provide an effective therapy for vascular diseases.

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