Cathepsin S is associated with degradation of collagen I in abdominal aortic aneurysm

VASA ◽  
2018 ◽  
Vol 47 (4) ◽  
pp. 285-293 ◽  
Author(s):  
Veronika Klaus ◽  
Fadwa Schmies ◽  
Christian Reeps ◽  
Matthias Trenner ◽  
Sarah Geisbüsch ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Heavy Chain ◽  
Protein Level ◽  
Mrna Level ◽  
Inflammatory Cells ◽  
Collagen I ◽  
Cathepsin S ◽  
Abdominal Aortic

Abstract. Background: Cathepsins have been described in the pathogenesis of abdominal aortic aneurysm (AAA), their exact role, especially in collagen degradation, is still unclear. The aim of the present study was therefore to analyse relevant cathepsins in human AAA tissue samples in relation to collagen I, III, and their degradation products. Materials and methods: Samples from 37 AAA patients obtained from elective open surgical repair and eight healthy non-aneurysmatic aortas from kidney donors were included. Expression of cathepsins B, D, K, L, S, cystatin C, collagen I and III, their degraded products C-Telopeptide of type 1 and 3 collagen (CTX-I, CTX-III), cellular markers for leukocytes (CD45), T cells (CD3), macrophage scavenger receptor-1 (MSR-1), synthetic, and contractile smooth muscle cells (SMCs) (smoothelin: SMTH, collagen I and III, myosin heavy chain: MHC, embryonic smooth muscle myosin heavy chain: SMemb) were determined at messenger RNA (mRNA) level, using SYBRGreen-based quantitative PCR and at protein level using enzyme-linked immunosorbent assay (ELISA). Results: Expression of cathepsins B, D, L, and S at mRNA level was significantly elevated in AAA compared to control aorta (1.7-fold, p = 0.025; 2.5-fold, p = 0.002; 2.6-fold, p = 0.034; and 7.0-fold, p = 0.003). Expression of cathepsin S correlated significantly with leukocytes and macrophages (ρ = 0.398, p = 0.033 and ρ = 0.422, p = 0.020), synthetic SMCs were significantly associated with cathepsins B, D, and L (ρ = 0.522, p = 0.003; ρ = 0.431, p = 0.015 and ρ = 0.467, p = 0.008). At protein level, cathepsins B and S were elevated in AAA compared to controls (5.4-fold, p = 0.001 and 7.3-fold, p < 0.001). Significant correlations were observed between collagen I, its degraded product, and cathepsin S (r = –0.350, p = 0.034 and r = +0.504, p < 0.001). Expression of cathepsin B was associated with SMCs, expression of cathepsin S with inflammatory cells. Conclusions: Particularly cathepsin S was associated with the degradation product of collagen I and thus might be involved in the progression of AAA. Furthermore, cathepsin S correlated with inflammatory cells.

scholarly journals Proteomic analysis of aortic smooth muscle cell secretions reveals an association of myosin heavy chain 11 with abdominal aortic aneurysm

2018 ◽  
Vol 315 (4) ◽  
pp. H1012-H1018 ◽  
Author(s):  
Utako Yokoyama ◽  
Noriaki Arakawa ◽  
Ryo Ishiwata ◽  
Shota Yasuda ◽  
Tomoyuki Minami ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Myosin Heavy Chain ◽  
Heavy Chain ◽  
Endovascular Aneurysm Repair ◽  
Aortic Diameter ◽  
Tunica Media ◽  
Abdominal Aortic ◽  
Aneurysm Repair

Abdominal aortic aneurysm (AAA) is a life-threatening disease, and no disease-specific circulating biomarkers for AAA screening are currently available. We have identified a smooth muscle cell (SMC)-specific biomarker for AAA. We cultured aneurysmal tunica media that were collected from eight patients undergoing elective open-repair surgeries. Secreted proteins in culture medium were subjected to liquid chromatography/tandem mass spectrometry. Myosin heavy chain 11 (myosin-11) was identified as a SMC-specific protein in the tunica media-derived secretions of all patients. We then examined myosin-11 protein concentrations by ELISA in plasma samples from patients with AAA ( n = 35) and age-matched healthy control subjects ( n = 34). Circulating myosin-11 levels were significantly higher in patients with AAA than control subjects. The area under the receiver-operating characteristic curve (AUC) of myosin-11 was 0.77, with a specificity of 65% at a sensitivity of 91%. Multivariate logistic regression analysis showed a significant association between the myosin-11 level and presence of AAA. When the myosin-11 level was combined with hypertension, it improved the prediction of AAA (AUC 0.88) more than hypertension per se. We then investigated the correlation between aortic diameter and circulating myosin-11 levels using AAA serum samples from patients undergoing endovascular aneurysm repair ( n = 20). Circulating myosin-11 levels were significantly correlated with maximum aortic diameter. Furthermore, changes in myosin-11 concentrations from the baseline 12 mo after endovascular aneurysm repair were associated with those in aortic diameter. These data suggest that circulating levels of myosin-11, which is a SMC-specific myosin isoform, may be useful as a biomarker for AAA. NEW & NOTEWORTHY Extensive studies have revealed that inflammation- or proteolysis-related proteins are proposed as biomarkers for abdominal aortic aneurysm (AAA). Changes in these protein concentrations are not specific for smooth muscle, which is a major part of AAA pathologies. Hence, no disease-specific circulating markers for AAA are currently available. We found, using secretome-based proteomic analysis on human AAA tunica media, that myosin heavy chain 11 was associated with AAA. Circulating myosin heavy chain 11 may be a new tissue-specific AAA marker.

Inflammatory Cells and Proteases in Abdominal Aortic Aneurysm and its Complications

2018 ◽  
Vol 19 (11) ◽  
pp. 1289-1296 ◽  
Author(s):  
Haiying Jiang ◽  
Takeshi Sasaki ◽  
Enze Jin ◽  
Masafumi Kuzuya ◽  
Xian Wu Cheng
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Inflammatory Cells ◽  
Abdominal Aortic

scholarly journals Rolipram Prevents the Formation of Abdominal Aortic Aneurysm (AAA) in Mice: PDE4B as a Target in AAA

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 460
Author(s):  
Saray Varona ◽  
Lídia Puertas ◽  
María Galán ◽  
Mar Orriols ◽  
Laia Cañes ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Inflammatory Cells ◽  
Progressive Increase ◽  
Phosphodiesterase 4 ◽  
Inflammatory Conditions ◽  
Abdominal Aortic ◽  
Threatening Condition ◽  
Life Threatening ◽  
Effective Therapeutic Strategy

Abdominal aortic aneurysm (AAA) is a common life-threatening condition characterized by exacerbated inflammation and the generation of reactive oxygen species. Pharmacological treatments to slow AAA progression or to prevent its rupture remain a challenge. Targeting phosphodiesterase 4 (PDE4) has been verified as an effective therapeutic strategy for an array of inflammatory conditions; however, no studies have assessed yet PDE4 in AAA. Here, we used angiotensin II (AngII)-infused apolipoprotein E deficient mice to study the involvement of the PDE4 subfamily in aneurysmal disease. PDE4B but not PDE4D was upregulated in inflammatory cells from both experimental and human AAA. The administration of the PDE4 selective inhibitor rolipram (3 mg/kg/day) to AngII-challenged mice (1000 ng/kg bodyweight/min) protected against AAA formation, limiting the progressive increase in the aortic diameter without affecting the blood pressure. The drug strongly attenuated the rise in vascular oxidative stress (superoxide anion) induced by AngII, and decreased the expression of inflammatory markers, as well as the recruitment of macrophages (MAC3+), lymphocytes (CD3+), and neutrophils (ELANE+) into the vessel wall. Rolipram also normalized the vascular MMP2 expression and MMP activity, preserving the elastin integrity and improving the vascular remodelling. These results point to PDE4B as a new therapeutic target for AAA.

scholarly journals Histochemical and immunohistochemical analysis of ruptured atherosclerotic abdominal aortic aneurysm wall

2010 ◽  
Vol 67 (12) ◽  
pp. 959-964 ◽  
Author(s):  
Irena Tanaskovic ◽  
Aleksandra Mladenovic-Mihailovic ◽  
Slavica Usaj-Knezevic ◽  
Vesna Stankovic ◽  
Aleksandar Aleksic ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Smooth Muscle Cells ◽  
Periodic Acid ◽  
Muscle Cells ◽  
Foam Cells ◽  
Abdominal Aortic ◽  
S 100 ◽  
The Media

Background/Aim. The main complication of the atherosclerotic abdominal aortic aneurism (AAA) is her rupture that begins with lesion in intima and rupture. The purpose of this work was to determine immunocytochemical and morphofunctional characteristics of the cells in aortic wall in ruptured atherosclerotic abdominal aortic aneurysm. Method. During the course of this study, 20 samples of atherosclerotic AAA were analyzed, all of them obtained during authopsy. The samples were fixed in 4% formalin and embedded in paraffin. Sections of 5 ?m thickness were stained histochemically (of Heidenhain azan stain and Periodic acid Schiff - PAS stain) and immunocytochemically using a DAKO LSAB+/HRP technique to identify ?-smooth muscle actin (?-SMA), vimentin, myosin heavy chains (MHC), desmin, S-100 protein, CD45 and CD68 (DAKO specification). Results. The results of our study showed that ruptured atherosclerotic AAA is characterized by a complete absence of endothelial cells, the disruption of basal membrane and internal elastic lamina, as well as a presence of the remains of hypocellular complicated atherosclerotic lesion in intima. On the plaque margins, as well as in the media, smooth muscle cells (SMCs) are present, which express a ?-SMA and vimentin (but without MHC or desmin expression), as well as leukocyte infiltration, and a large number of foam cells. Some of the foam cells show a CD68-immunoreactivity, while the others show vimentin- and S-100 protein-immunoreactivity. Media is thinned out with a disorganized elastic lamellas, while adventitia is characterized by inflammatory inflitrate (infection). Conclusion. Rupture of aneurysm occurs from the primary intimal disruption, which spreads into thinned out media and adventitia. Rupture is caused by unstable atherom, hypocellularity, loss of contractile characteristics of smooth muscle cells in intima and media, neovascularization of the media, as well as by the activity of the macrophages in the lesion.

scholarly journals SM22α Loss Contributes to Apoptosis of Vascular Smooth Muscle Cells via Macrophage-Derived circRasGEF1B

2021 ◽  
Vol 2021 ◽  
pp. 1-20
Author(s):  
Pin Lv ◽  
Ya-Juan Yin ◽  
Peng Kong ◽  
Li Cao ◽  
Hao Xi ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Vascular Smooth Muscle ◽  
Inflammatory Cell ◽  
Activated Macrophages ◽  
Abdominal Aortic ◽  
Specific Manner ◽  
Higher Sensitivity

Vascular smooth muscle cell (VSMC) apoptosis is a major defining feature of abdominal aortic aneurysm (AAA) and mainly caused by inflammatory cell infiltration. Smooth muscle (SM) 22α prevents AAA formation through suppressing NF-κB activation. However, the role of SM22α in VSMC apoptosis is controversial. Here, we identified that SM22α loss contributed to apoptosis of VSMCs via activation of macrophages. Firstly, deficiency of SM22α enhanced the interaction of VSMCs with macrophages. Macrophages were retained and activated by Sm22α-/- VSMCs via upregulating VCAM-1 expression. The ratio of apoptosis was increased by 1.62-fold in VSMCs treated with the conditional media (CM) from activated RAW264.7 cells, compared to that of the control CM ( P < 0.01 ), and apoptosis of Sm22α-/- VSMCs was higher than that of WT VSMCs ( P < 0.001 ). Next, circRasGEF1B from activated macrophages was delivered into VSMCs promoting ZFP36 expression via stabilization of ZFP36 mRNA. Importantly, circRasGEF1B, as a scaffold, guided ZFP36 to preferentially bind to and decay Bcl-2 mRNA in a sequence-specific manner and triggered apoptosis of VSMCs, especially in Sm22α-/- VSMCs. These findings reveal a novel mechanism by which the circRasGEF1B-ZFP36 axis mediates macrophage-induced VSMC apoptosis via decay of Bcl-2 mRNA, whereas Sm22α-/- VSMCs have a higher sensitivity to apoptosis.

Peri-Adventitial Delivery of Smooth Muscle Cells in Porous Collagen Scaffolds for Treatment of Experimental Abdominal Aortic Aneurysm

2021 ◽  
Author(s):  
Joscha Mulorz ◽  
Mahdis Shayan ◽  
Caroline Hu ◽  
Cynthia Alcazar ◽  
Alex H.P Chan ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Vessel Wall ◽  
Muscle Cells ◽  
Collagen Scaffolds ◽  
Abdominal Aortic ◽  
Direct Delivery

Abdominal aortic aneurysm (AAA) is associated with the loss of vascular smooth muscle cells (SMCs) within the vessel wall. Direct delivery of therapeutic cells is challenging due to impaired mechanical...

scholarly journals Genetic and Epigenetic Mechanisms Underlying Vascular Smooth Muscle Cell Phenotypic Modulation in Abdominal Aortic Aneurysm

2020 ◽  
Vol 21 (17) ◽  
pp. 6334
Author(s):  
Rijan Gurung ◽  
Andrew Mark Choong ◽  
Chin Cheng Woo ◽  
Roger Foo ◽  
Vitaly Sorokin
Keyword(s):  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Smooth Muscle Cells ◽  
Aortic Wall ◽  
Epigenetic Mechanisms ◽  
Phenotypic Modulation ◽  
Abdominal Aortic

Abdominal aortic aneurysm (AAA) refers to the localized dilatation of the infra-renal aorta, in which the diameter exceeds 3.0 cm. Loss of vascular smooth muscle cells, degradation of the extracellular matrix (ECM), vascular inflammation, and oxidative stress are hallmarks of AAA pathogenesis and contribute to the progressive thinning of the media and adventitia of the aortic wall. With increasing AAA diameter, and left untreated, aortic rupture ensues with high mortality. Collective evidence of recent genetic and epigenetic studies has shown that phenotypic modulation of smooth muscle cells (SMCs) towards dedifferentiation and proliferative state, which associate with the ECM remodeling of the vascular wall and accompanied with increased cell senescence and inflammation, is seen in in vitro and in vivo models of the disease. This review critically analyses existing publications on the genetic and epigenetic mechanisms implicated in the complex role of SMCs within the aortic wall in AAA formation and reflects the importance of SMCs plasticity in AAA formation. Although evidence from the wide variety of mouse models is convincing, how this knowledge is applied to human biology needs to be addressed urgently leveraging modern in vitro and in vivo experimental technology.

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.

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