Extracellular matrix metalloproteinase inducer (EMMPRIN) is present in smooth muscle cells of human aneurysmal aorta and is induced by angiotensin II in vitro

2009 ◽  
Vol 116 (11) ◽  
pp. 819-826 ◽  
Author(s):  
Xiao-feng Chen ◽  
Jian-an Wang ◽  
Jun Hou ◽  
Chun Gui ◽  
Li-jiang Tang ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Aortic Dissection ◽  
Matrix Metalloproteinase ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Extracellular Matrix Metalloproteinase Inducer

The aim of the present study was to determine whether EMMPRIN (extracellular matrix metalloproteinase inducer) is present and is up-regulated in human aneurysmal aortas, and to assess a possible association with AngII (angiotensin II)-induced aneurysm formation. The presence of EMMPRIN was assessed in 41 surgical specimens from patients with a TAA (thoracic aortic aneurysm) (Type A aortic dissection, n=12; Type B aortic dissection, n=7; and TAA without dissection, n=7) or an AAA (abdominal aortic aneurysm, n=15) by immunohistochemistry. EMMPRIN expression in aortic aneurysm tissues was compared with 12 aortas obtained during autopsy (free of any vascular diseases), and scored for both staining intensity and the percentage of vascular cells stained. EMMPRIN protein levels in cultured human aortic SMCs (smooth muscle cells) following stimulation of AngII were analysed by Western blotting. Significant EMMPRIN immunoreactivity was detected in aortic aneurysm lesions from patients with TAAs and AAAs. In the aneurysmal wall, α-actin-positive SMCs were the main source of EMMPRIN. The frequency of EMMPRIN overexpression was significantly higher (P=0.026) in TAAs with dissection (68.4%) than TAAs without dissection (14.3%). AngII stimulation up-regulated the expression of EMMPIRN in cultured human aortic SMCs, which was suppressed by the addition of the AT1R (AngII type 1 receptor) antagonist losartan. In conclusion, the present study is the first to report the expression of EMMPRIN in aortic aneurysmal diseases, and we speculate that EMMPRIN may be important in the pathogenesis of these diseases. Whether these abnormalities are potential therapeutic targets deserve further investigation.

scholarly journals Deficiency in Aim2 affects viability and calcification of vascular smooth muscle cells from murine aortas and Angiotensin-II induced aortic aneurysms

2020 ◽  
Author(s):  
Markus Wortmann ◽  
Muhammad Arshad ◽  
Maani Hakimi ◽  
Dittmar Böckler ◽  
Susanne Dihlmann
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Mouse Model ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells

Abstract Background: Phenotypic transformation of vascular smooth muscle cells is a key element in vascular remodeling and aortic aneurysm growth. Previously, deletion of several inflammasome components decreased formation of aortic aneurysm (AA) in the Angiotensin II (AngII) -induced mouse model. We hypothesized that the inflammasome sensor Absent in melanoma 2 (Aim2) might affect the phenotype of vascular smooth muscle cells (VSMC), thereby reducing AA formation. Methods : Aim2-/- mice and wild-type (WT) C57Bl/6J mice were used as an animal model. VSMC were isolated from 6 months old mice and grown in vitro . Young (passage 3-5) and senescent (passage 7-12) cells were analyzed in vitro for calcification in mineralization medium by Alizarin Red S staining. Expression of calcification and inflammatory markers were studied by real-time RT-PCR and Western blotting, release of cytokines was determined by ELISA. To induce AA, osmotic mini-pumps loaded with AngII (1500 ng/kg bodyweight/min) were implanted for 28 days in male mice at 6 months of age. Results : Compared with VSMC from WT mice, VSMC isolated from Aim2-/- mice were larger, less viable, and underwent stronger calcification in mineralization medium, along with induction of Bmp4 and repression of Tnfsf11/Rankl gene expression. In addition, Aim2 deficiency was associated with reduced inflammasome gene expression and release of Interleukin-6. Using the mouse model of AngII induced AA, Aim2 deficiency reduced AA incidence to 48.4% (15/31) in Aim2-/- mice versus 76.5% (13/17) in WT mice. In contrast to Aim2-/- mice, AA from WT mice expressed significantly increased levels of alpha-smooth muscle actin/ Acta2 , indicating tissue remodeling. Reduced cell proliferation in Aim2-/- mice was indicated by significantly increased p16ink4a/ Cdkn2a expression in untreated and AngII-infused aortas, and by significantly lower amounts of proliferating (Ki67 positive) VSMC in AngII-infused Aim2-/- mice. Conclusions: Our results suggest a role for Aim2 in regulating VSMC proliferation and transition to an osteoblast-like or osteoclast-like phenotype, thereby modulating the response of VSMC in aortic remodeling and AA Formation.

scholarly journals Deficiency in Aim2 affects viability and calcification of vascular smooth muscle cells from murine aortas and Angiotensin-II induced aortic aneurysms

2020 ◽  
Author(s):  
Markus Wortmann ◽  
Muhammad Arshad ◽  
Maani Hakimi ◽  
Dittmar Böckler ◽  
Susanne Dihlmann
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Mouse Model ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells

Abstract Background: Phenotypic transformation of vascular smooth muscle cells is a key element in vascular remodeling and aortic aneurysm growth. Previously, deletion of several inflammasome components decreased formation of aortic aneurysm (AA) in the Angiotensin II (AngII) -induced mouse model. We hypothesized that the inflammasome sensor Absent in melanoma 2 (Aim2) might affect the phenotype of vascular smooth muscle cells (VSMC), thereby reducing AA formation. Methods: Aim2-/- mice and wild-type (WT) C57Bl/6J mice were used as an animal model. VSMC were isolated from 6 months old mice and grown in vitro. Young (passage 3-5) and senescent (passage 7-12) cells were analyzed in vitro for calcification in mineralization medium by Alizarin Red S staining. Expression of calcification and inflammatory markers were studied by real-time RT-PCR and Western blotting, release of cytokines was determined by ELISA. To induce AA, osmotic mini-pumps loaded with AngII (1500 ng/kg bodyweight/min) were implanted for 28 days in male mice at 6 months of age.Results: Compared with VSMC from WT mice, VSMC isolated from Aim2-/- mice were larger, less viable, and underwent stronger calcification in mineralization medium, along with induction of Bmp4 and repression of Tnfsf11/Rankl gene expression. In addition, Aim2 deficiency was associated with reduced inflammasome gene expression and release of Interleukin-6. Using the mouse model of AngII induced AA, Aim2 deficiency reduced AA incidence to 48.4% (15/31) in Aim2-/- mice versus 76.5% (13/17) in WT mice. In contrast to Aim2-/- mice, AA from WT mice expressed significantly increased levels of alpha-smooth muscle actin/Acta2, indicating tissue remodeling. Reduced cell proliferation in Aim2-/- mice was indicated by significantly increased p16ink4a/Cdkn2a expression in untreated and AngII-infused aortas, and by significantly lower amounts of proliferating (Ki67 positive) VSMC in AngII-infused Aim2-/- mice. Conclusions: Our results suggest a role for Aim2 in regulating VSMC proliferation and transition to an osteoblast-like or osteoclast-like phenotype, thereby modulating the response of VSMC in aortic remodeling and AA formation.

scholarly journals Deficiency in Aim2 affects viability and calcification of vascular smooth muscle cells from murine aortas and angiotensin-II induced aortic aneurysms

2020 ◽  
Vol 26 (1) ◽  
Author(s):  
Markus Wortmann ◽  
Muhammad Arshad ◽  
Maani Hakimi ◽  
Dittmar Böckler ◽  
Susanne Dihlmann
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Mouse Model ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells

Abstract Background Phenotypic transformation of vascular smooth muscle cells is a key element in vascular remodeling and aortic aneurysm growth. Previously, deletion of several inflammasome components decreased formation of aortic aneurysm (AA) in the Angiotensin II (AngII) -induced mouse model. We hypothesized that the inflammasome sensor Absent in melanoma 2 (Aim2) might affect the phenotype of vascular smooth muscle cells (VSMC), thereby reducing AA formation. Methods Aim2−/− mice and wild-type (WT) C57Bl/6 J mice were used as an animal model. VSMC were isolated from 6 months old mice and grown in vitro. Young (passage 3–5) and senescent (passage 7–12) cells were analyzed in vitro for calcification in mineralization medium by Alizarin Red S staining. Expression of calcification and inflammatory markers were studied by real-time RT-PCR and Western blotting, release of cytokines was determined by ELISA. To induce AA, osmotic mini-pumps loaded with AngII (1500 ng/kg bodyweight/min) were implanted for 28 days in male mice at 6 months of age. Results Compared with VSMC from WT mice, VSMC isolated from Aim2−/− mice were larger, less viable, and underwent stronger calcification in mineralization medium, along with induction of Bmp4 and repression of Tnfsf11/Rankl gene expression. In addition, Aim2 deficiency was associated with reduced inflammasome gene expression and release of Interleukin-6. Using the mouse model of AngII induced AA, Aim2 deficiency reduced AA incidence to 48.4% (15/31) in Aim2−/− mice versus 76.5% (13/17) in WT mice. In contrast to Aim2−/− mice, AA from WT mice expressed significantly increased levels of alpha-smooth muscle actin/Acta2, indicating tissue remodeling. Reduced cell proliferation in Aim2−/− mice was indicated by significantly increased p16ink4a/Cdkn2a expression in untreated and AngII-infused aortas, and by significantly lower amounts of proliferating (Ki67 positive) VSMC in AngII-infused Aim2−/− mice. Conclusions Our results suggest a role for Aim2 in regulating VSMC proliferation and transition to an osteoblast-like or osteoclast-like phenotype, thereby modulating the response of VSMC in aortic remodeling and AA formation.

Angiotensin II modulates frizzled-2 receptor expression in rat vascular smooth muscle cells

2005 ◽  
Vol 108 (6) ◽  
pp. 523-530 ◽  
Author(s):  
Giovanna CASTOLDI ◽  
Serena REDAELLI ◽  
Willy M. M. van de GREEF ◽  
Cira R. T. di GIOIA ◽  
Giuseppe BUSCA ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Ang Ii ◽  
Aortic Smooth Muscle

Ang II (angiotensin II) has multiple effects on vascular smooth muscle cells through the modulation of different classes of genes. Using the mRNA differential-display method to investigate gene expression in rat aortic smooth muscle cells in culture in response to 3 h of Ang II stimulation, we observed that Ang II down-regulated the expression of a member of the family of transmembrane receptors for Wnt proteins that was identified as Fzd2 [Fzd (frizzled)-2 receptor]. Fzds are a class of highly conserved genes playing a fundamental role in the developmental processes. In vitro, time course experiments demonstrated that Ang II induced a significant increase (P<0.05) in Fzd2 expression after 30 min, whereas it caused a significant decrease (P<0.05) in Fzd2 expression at 3 h. A similar rapid up-regulation after Ang II stimulation for 30 min was evident for TGFβ1 (transforming growth factor β1; P<0.05). To investigate whether Ang II also modulated Fzd2 expression in vivo, exogenous Ang II was administered to Sprague–Dawley rats (200 ng·kg−1 of body weight·min−1; subcutaneously) for 1 and 4 weeks. Control rats received normal saline. After treatment, systolic blood pressure was significantly higher (P<0.01), whereas plasma renin activity was suppressed (P<0.01) in Ang II- compared with the saline-treated rats. Ang II administration for 1 week did not modify Fzd2 expression in aorta of Ang II-treated rats, whereas Ang II administration for 4 weeks increased Fzd2 mRNA expression (P<0.05) in the tunica media of the aorta, resulting in a positive immunostaining for fibronectin at this time point. In conclusion, our data demonstrate that Ang II modulates Fzd2 expression in aortic smooth muscle cells both in vitro and in vivo.

scholarly journals MT1-matrix metalloproteinase directs arterial wall invasion and neointima formation by vascular smooth muscle cells

2005 ◽  
Vol 202 (5) ◽  
pp. 663-671 ◽  
Author(s):  
Sergey Filippov ◽  
Gerald C. Koenig ◽  
Tae-Hwa Chun ◽  
Kevin B. Hotary ◽  
Ichiro Ota ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Smooth Muscle ◽  
Matrix Metalloproteinase ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Arterial Wall ◽  
Neointimal Hyperplasia ◽  
Muscle Cells

During pathologic vessel remodeling, vascular smooth muscle cells (VSMCs) embedded within the collagen-rich matrix of the artery wall mobilize uncharacterized proteolytic systems to infiltrate the subendothelial space and generate neointimal lesions. Although the VSMC-derived serine proteinases, plasminogen activator and plasminogen, the cysteine proteinases, cathepsins L, S, and K, and the matrix metalloproteinases MMP-2 and MMP-9 have each been linked to pathologic matrix-remodeling states in vitro and in vivo, the role that these or other proteinases play in allowing VSMCs to negotiate the three-dimensional (3-D) cross-linked extracellular matrix of the arterial wall remains undefined. Herein, we demonstrate that VSMCs proteolytically remodel and invade collagenous barriers independently of plasmin, cathepsins L, S, or K, MMP-2, or MMP-9. Instead, we identify the membrane-anchored matrix metalloproteinase, MT1-MMP, as the key pericellular collagenolysin that controls the ability of VSMCs to degrade and infiltrate 3-D barriers of interstitial collagen, including the arterial wall. Furthermore, genetic deletion of the proteinase affords mice with a protected status against neointimal hyperplasia and lumen narrowing in vivo. These studies suggest that therapeutic interventions designed to target MT1-MMP could prove beneficial in a range of human vascular disease states associated with the destructive remodeling of the vessel wall extracellular matrix.

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