scholarly journals Expression and role of lumican in acute aortic dissection: A human and mouse study

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0255238
Author(s):  
Shao-Wei Chen ◽  
Shing-Hsien Chou ◽  
Ying-Chang Tung ◽  
Fu-Chih Hsiao ◽  
Chien-Te Ho ◽  
...  
Keyword(s):  
Aortic Dissection ◽  
Aortic Rupture ◽  
Expression Patterns ◽  
Ang Ii ◽  
Mice Model ◽  
Tissue Integrity ◽  
Potential Biomarker ◽  
Life Threatening ◽  
Mouse Study

Introduction Aortic dissection (AD) is a life-threatening emergency, and lumican (LUM) is a potential Biomarker for AD diagnosis. We investigated LUM expression patterns in patients with AD and explored the molecular functions of Lum in AD mice model. Methods LUM expression patterns were analyzed using aortic tissues of AD patients, and serum soluble LUM (s-LUM) levels were compared between patients with acute AD (AAD) and chronic AD (CAD). Lum-knockout (Lum−/−) mice were challenged with β-aminopropionitrile (BAPN) and angiotensin II (Ang II) to induce AD. The survival rate, AD incidence, and aortic aneurysm (AA) in these mice were compared with those in BAPN–Ang II–challenged wildtype (WT) mice. Tgf-β/Smad2, Mmps, Lum, and Nox expression patterns were examined. Results LUM expression was detected in the intima and media of the ascending aorta in patients with AAD. Serum s-LUM levels were significantly higher in patients with AAD than CAD. Furthermore, AD-associated mortality and thoracic aortic rupture incidence were significantly higher in the Lum−/− AD mice than in the WT AD mice. However, no significant pathologic changes in AA were observed in the Lum−/− AD mice compared with the WT AD mice. The BAPN–Ang II–challenged WT and Lum−/− AD mice had higher Tgf-β, p-Smad2, Mmp2, Mmp9, and Nox4 levels than those of non-AD mice. We also found that Lum expression was significantly higher in the BAPN-Ang II–challenged WT in comparison to the unchallenged WT mice. Conclusion LUM expression was altered in patients with AD display increased s-LUM in blood, and Lum−/− mice exhibited augmented AD pathogenesis. These findings support the notion that LUM is a biomarker signifying the pathogenesis of injured aorta seen in AAD. The presence of LUM is essential for maintenance of connective tissue integrity. Future studies should elucidate the mechanisms underlying LUM association in aortic changes.

Abstract P141: GYY4137, a H 2 S Donor, Normalizes miR-132 Targeted Sirt1 and Ace2 Expression to Improve Kidney Function in Hypertension

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Gregory Weber ◽  
Sathnur Pushpakumar ◽  
Utpal Sen
Keyword(s):  
Blood Flow ◽  
Kidney Function ◽  
Expression Patterns ◽  
Sirtuin 1 ◽  
Ang Ii ◽  
Cellular Processes ◽  
Physiological Processes ◽  
Epigenetic Gene Silencing ◽  
Increased Blood Flow

MicroRNAs regulate several physiological processes and are implicated in various pathologies, including hypertension. Previous work indicates miR-132 targets Sirtuin 1 (Sirt1), a histone deacetylase and regulator of epigenetic gene silencing in various cellular processes. Sirt1 is expressed in the kidney; however, its role in hypertensive kidney and whether it is regulated by physiological gaseous molecules, such as hydrogen sulfide (H 2 S), is not known. In this study, we sought to determine the role of miR-132 in regulating Sirt1, Ace2 and At1 in hypertensive kidney and whether H 2 S donor, GYY4137 (GYY), could reverse these effects and mitigates renal dysfunction. Wild-type mice were treated without or with Ang-II (1000 ng/Kg/Min) and GYY (133 μM) for 4 weeks. Quantitative PCR, Western blot, and immunofluorescence assays were performed. Increased expression levels of miR-132 in hypertensive mice (3.79 fold vs control) were reduced in mice receiving GYY treatment (2.43 fold vs control). Sirt1 expression was reduced (-1.15 fold) in Ang-II mice but was upregulated in GYY (1.25 fold) and Ang-II+GYY (1.9 fold) groups. A similar effect was seen with Sirt1 protein where the expression was increased in animals treated with GYY and Ang-II+GYY (1.16, 1.03 respectively) compared to Ang-II (0.47). Ace2 in Ang-II+GYY (0.45) was increased compared to Ang-II (0.17), while At1 was reduced (0.46) compared to Ang-II (0.86). Immunofluorescence showed decreased signal of Sirt1 in the glomerulus in Ang-II mice and increased At1 in the blood vessels surrounding the glomerulus, leading to constriction of renal artery, decreased blood flow, and kidney dysfunction. These effects were alleviated in mice treated with GYY. Our data suggests that upregulation of miR-132 in hypertensive kidney decreases Sirt1 and Ace2 expression, leading to increased Ang-II signaling through the At1 receptor and GYY supplementation reverses these expression patterns, leading to increased blood flow and kidney function.

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.

scholarly journals Aortic Dissection in a Pregnant Patient without Other Risk Factors

2019 ◽  
Vol 2019 ◽  
pp. 1-3
Author(s):  
Priya V. Patel ◽  
Raanan Alter ◽  
Recia Frenn ◽  
Thaddeus P. Waters
Keyword(s):  
Risk Factors ◽  
Aortic Dissection ◽  
Aortic Rupture ◽  
Treatment Options ◽  
Pregnant Patient ◽  
Physical Exam ◽  
Vascular Events ◽  
Increased Risk ◽  
Threatening Condition ◽  
Life Threatening

Background. An aortic dissection is a life-threatening condition in which the intima of the artery tears causing separation of the intima and media. Pregnancy places women at a significantly increased risk of common vascular events including venous thromboembolism, myocardial infarction, and stroke, while also increasing the risk of rarer vascular events such as aortic dissection and aortic rupture. Case. A 30-year-old previously healthy multiparous woman presenting at 36 weeks of pregnancy with a Type A aortic dissection. She underwent a combined emergent cesarean delivery followed by repair of her aortic root. Conclusions. Aortic dissection should be high on the differential for pregnant patients presenting with the characteristic complaints and physical exam findings given the high mortality rate associated with this vascular event. Teaching Points. (1) This report reviews the characteristic presentation, risk factors, and physical exam findings in a patient with an aortic dissection. (2) The report includes treatment options for pregnant patients based on the classification of the dissection.

scholarly journals Single-Cell Transcriptome Profiles Reveal Fibrocytes as Potential Targets of Cell Therapies for Abdominal Aortic Aneurysm

2021 ◽  
Vol 8 ◽  
Author(s):  
Bolun Li ◽  
Xiaomin Song ◽  
Wenjun Guo ◽  
Yangfeng Hou ◽  
Huiyuan Hu ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Single Cell ◽  
Aortic Rupture ◽  
Ang Ii ◽  
Cell Therapies ◽  
Abdominal Aortic ◽  
Life Threatening ◽  
Cell Transcriptome ◽  
Therapy Target

Abdominal aortic aneurysm (AAA) is potentially life-threatening in aging population due to the risk of aortic rupture and a lack of optimal treatment. The roles of different vascular and immune cells in AAA formation and pathogenesis remain to be future characterized. Single-cell RNA sequencing was performed on an angiotensin (Ang) II-induced mouse model of AAA. Macrophages, B cells, T cells, fibroblasts, smooth muscle cells and endothelial cells were identified through bioinformatic analyses. The discovery of multiple subtypes of macrophages, such as the re-polarization of Trem2+Acp5+ osteoclast-like and M2-like macrophages toward the M1 type macrophages, indicates the heterogenous nature of macrophages during AAA development. More interestingly, we defined CD45+COL1+ fibrocytes, which was further validated by flow cytometry and immunostaining in mouse and human AAA tissues. We then reconstituted these fibrocytes into mice with Ang II-induced AAA and found the recruitment of these fibrocytes in mouse AAA. More importantly, the fibrocyte treatment exhibited a protective effect against AAA development, perhaps through modulating extracellular matrix production and thus enhancing aortic stability. Our study reveals the heterogeneity of macrophages and the involvement of a novel cell type, fibrocyte, in AAA. Fibrocyte may represent a potential cell therapy target for AAA.

Abstract 351: Focal Adhesion Kinase Promotes Tissue Destruction in Aortic Dissection in Mice

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Ryohei Majima ◽  
Hiroki Aoki ◽  
Eichi Nakao ◽  
Yohei Hashimoto ◽  
Sohei Ito ◽  
...  
Keyword(s):  
Aortic Dissection ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Suppressive Effect ◽  
Lesion Length ◽  
Ang Ii ◽  
Tissue Destruction ◽  
Potential Therapeutic Target ◽  
Mouse Aorta

Aortic dissection (AD) is a fatal disease due to the sudden destruction of the aortic medial layer. Currently, Molecular pathogenesis of AD is unknown. We investigated the role of focal adhesion kinase (FAK), a mechanosensitive signal transducer, in AD pathogenesis. We created a mouse model of AD with a continuous infusion of beta-aminopropionitrile (150 mg/kg/day), a collagen crosslink inhibitor, and angiotensin II (1,000 ng/kg/min) (BAPN + Ang II) by osmotic pumps. This AD model showed about 60% mortality within 2 weeks due to AD rupture. Immunohistochemical staining for activated FAK revealed that FAK was inactive in normal mouse aorta, but was strongly activated in the aortic walls after BAPN + Ang II infusion. Immunofluorescence staining showed that FAK was activated mainly in smooth muscle cells after the BAPN + Ang II challenge. Western blot analysis revealed that FAK was activated in 3 days after BAPN + Ang II infusion before AD development, followed by transient reduction at day 7, and re-activation after AD development at day 14. We examined the effect of PND-1186, an orally available FAK inhibitor, on the severity as determined by the AD lesion length and the mortality of AD. Mice were administered with either vehicle or PND-1186 (150 mg/kg twice daily by oral gavage) during the BAPN + Ang II challenge (n=20 for each group). Administration of PND-1186 resulted in significant reduction in the lesion length of AD (vehicle; 12.5 ± 1.65 mm, PND; 7.46 ± 1.88 mm, P<0.05). The suppressive effect of PND-1186 was most significant in the aortic arch (vehicle; 2.13 ± 0.29 mm, PND; 0.85 ± 0.22 mm, P<0.01). Furthermore, PND-1186 significantly improved the survival rate of mice from 40.0% to 80.0% (P<0.01). Transcriptome analysis indicated that destruction and inflammation of tissue were suppressed by PND-1186 administration. These findings indicated that FAK plays an important role in AD pathogenesis, possibly by transducing the pathological stress to the tissue destructive response in the aortic walls. We propose that FAK is a potential therapeutic target to limit the fatal destruction of aortic walls in AD.

Downregulation of apelin in the human placental chorionic villi from preeclamptic pregnancies

2015 ◽  
Vol 309 (10) ◽  
pp. E852-E860 ◽  
Author(s):  
Liliya M. Yamaleyeva ◽  
Mark C. Chappell ◽  
K. Bridget Brosnihan ◽  
Lauren Anton ◽  
David L. Caudell ◽  
...  
Keyword(s):  
Low Dose ◽  
Expression Patterns ◽  
Ang Ii ◽  
Chorionic Villi ◽  
Angiotensin Converting Enzyme 2 ◽  
Predominant Form ◽  
Pooled Samples ◽  
In Pregnancy

The role of the endogenous apelin system in pregnancy is not well understood. Apelin's actions in pregnancy are further complicated by the expression of multiple forms of the peptide. Using radioimmunoassay (RIA) alone, we established the expression of apelin content in the chorionic villi of preeclamptic (PRE) and normal pregnant women (NORM) at 36–38 wk of gestation. Total apelin content was lower in PRE compared with NORM chorionic villi (49.7 ± 3.4 vs. 72.3 ± 9.8 fmol/mg protein; n = 20–22) and was associated with a trend for lower preproapelin mRNA in the PRE. Further characterization of apelin isoforms by HPLC-RIA was conducted in pooled samples from each group. The expression patterns of apelin peptides in NORM and PRE villi revealed little or no apelin-36 or apelin-17. Pyroglutamate apelin-13 [(Pyr1)-apelin-13] was the predominant form of the peptide in NORM and PRE villi. Angiotensin-converting enzyme 2 (ACE2) activity was higher in PRE villi (572.0 ± 23.0 vs. 485.3 ± 24.8 pmol·mg−1·min−1; n = 18–22). A low dose of ANG II (1 nM; 2 h) decreased apelin release in NORM villous explants that was blocked by the ANG II receptor 1 (AT1) antagonist losartan. Moreover, losartan enhanced apelin release above the 2-h baseline levels in both NORM and PRE villi ( P < 0.05). In summary, these studies are the first to demonstrate the lower apelin content in human placental chorionic villi of PRE subjects using quantitative RIA. (Pyr1)-apelin-13 is the predominant form of endogenous apelin in the chorionic villi of NORM and PRE. The potential mechanism of lower apelin expression in the PRE villi may involve a negative regulation of apelin by ANG II.

The Role of miR-107 as a Potential Biomarker and Cellular Factor for Acute Aortic Dissection

2020 ◽  
Vol 39 (10) ◽  
pp. 1895-1906
Author(s):  
Zanxin Wang ◽  
Xianmian Zhuang ◽  
Bailang Chen ◽  
Dongjie Feng ◽  
Gang Li ◽  
...  
Keyword(s):  
Aortic Dissection ◽  
Acute Aortic Dissection ◽  
Cellular Factor ◽  
Potential Biomarker

scholarly journals Hybrid Stepwise External Wrapping for Type A Acute Aortic Dissection with Cerebral Malperfusion

2020 ◽  
Author(s):  
Yoshihiro Suematsu ◽  
Satoshi Nishi ◽  
Daisuke Arima ◽  
Akihiro Yoshimoto
Keyword(s):  
Aortic Dissection ◽  
Acute Aortic Dissection ◽  
Aortic Rupture ◽  
False Lumen ◽  
Type A ◽  
Good Physical Condition ◽  
Threatening Condition ◽  
Valve Insufficiency ◽  
Life Threatening ◽  
Cerebral Malperfusion

Abstract Background: Acute aortic dissection (AAD) is a life-threatening condition which can lead to coronary, brachiocephalic or branch vessel malperfusion, as well as aortic valve insufficiency, or aortic rupture. Mortality of surgical treatment in high-risk or elderly patients with Type A AAD (TAAAD) still remains high, and treatment for such patients remains controversial. We report a successful treatment of TAAAD with a communicating false lumen in a 60-year-old man with acute hemi-cerebral malperfusion. Case presentation: The ascending aorta was wrapped with stepwise external wrapping (SEW) procedure, and subsequent thoracic endovascular aortic repair (TEVAR) was successfully performed. The patient was discharged in good physical condition without any complications. Conclusions: Hybrid therapy with SEW and TEVAR with TAAAD associated with major cerebral malperfusion should be considered, especially in patients for whom open surgery is extremely risky.

Role of c-Abl in Ang II-induced aortic dissection formation: Potential regulatory efficacy on phenotypic transformation and apoptosis of VSMCs

Life Sciences ◽  
2020 ◽  
Vol 256 ◽  
pp. 117882
Author(s):  
Xianwu Zhou ◽  
Jiancheng Cheng ◽  
Zerui Chen ◽  
Huadong Li ◽  
Shu Chen ◽  
...  
Keyword(s):  
Aortic Dissection ◽  
Ang Ii ◽  
Formation Potential ◽  
Phenotypic Transformation

scholarly journals AT1R Regulates Macrophage Polarization Through YAP and Regulates Aortic Dissection Incidence

2021 ◽  
Vol 12 ◽  
Author(s):  
Xinhao Wang ◽  
Hongpeng Zhang ◽  
Yangyang Ge ◽  
Long Cao ◽  
Yuan He ◽  
...  
Keyword(s):  
Aortic Dissection ◽  
Macrophage Polarization ◽  
Culture Conditions ◽  
Ang Ii ◽  
Mice Model ◽  
M1 Macrophages ◽  
M1 Polarization ◽  
Inflammatory Chemokines ◽  
Inflammatory Effect

Aortic dissection (AD) is one of the most fatal cardiovascular emergency. At the anatomical level, AD occurs due to the formation of intimal tears. However, the molecular mechanism underlying this phenomenon remains unknown. Angiotensin II (Ang II) is a important effector in the development of cardiovascular disease that acts through binding to angiotensin type 1 receptor (AT1R). Yes-associated protein (YAP) was recently recognized as a key protein in macrophage activation. To determine whether AT1R and YAP are involved in macrophage-induced endothelial cell (EC) inflammation and AD incidence, we co-cultured THP-1 cells and HAECs in transwell chambers under different culture conditions and apply different conditions to the AD mice model. The results showed that Ang II promoted macrophage M1 polarization and adhesion, upregulated YAP phosphorylation, and induced EC injury that was related to increased levels of multiple pro-inflammatory chemokines. Blocking AT1R function pharmacologically or by transfection with AT1R siRNA can reduce the pro-inflammatory effect induced by Ang II. In addition, siRNA knock down of YAP expression further aggravated the pro-inflammatory effects of Ang II. Treatment with ARB effectively alleviated these pro-inflammatory effects. In the mice AD model, ARB effectively reduced the incidence of AD in mice, decreased M1 macrophages infiltration and AT1R content in the aortic wall and increased the tissue content of YAP. We found that AT1R induces YAP phosphorylation through binding to Ang II, and further promotes macrophage M1 polarization and adhesion to ECs. ARB reduces the incidence of AD in mice and affect macrophage polarization in mice aorta.

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