scholarly journals The Inhibition of Prolyl Oligopeptidase as New Target to Counteract Chronic Venous Insufficiency: Findings in a Mouse Model

Biomedicines ◽  
2020 ◽  
Vol 8 (12) ◽  
pp. 604
Author(s):  
Giovanna Casili ◽  
Marika Lanza ◽  
Sarah Adriana Scuderi ◽  
Salvatore Messina ◽  
Irene Paterniti ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Chronic Venous Insufficiency ◽  
Venous Insufficiency ◽  
Smooth Muscle Actin ◽  
Muscle Actin ◽  
Tgf Beta ◽  
Prolyl Oligopeptidase ◽  
Culture Study ◽  
Tissue Block

(1) Background: Chronic venous insufficiency (CVI) is a common disorder related to functional and morphological abnormalities of the venous system. Inflammatory processes and angiogenesis alterations greatly concur to the onset of varicose vein. KYP-2047 is a selective inhibitor of prolyl oligopeptidase (POP), a serine protease involved in the release of pro-angiogenic molecules. The aim of the present study is to evaluate the capacity of KYP-2047 to influence the angiogenic and inflammatory mechanisms involved in the pathophysiology of CVI. (2) Methods: An in vivo model of CVI-induced by saphene vein ligation (SVL) and a tissue block culture study were performed. Mice were subjected to SVL followed by KYP-2047 treatment (intraperitoneal, 10 mg/kg) for 7 days. Histological analysis, Masson’s trichrome, Van Gieson staining, and mast cells evaluation were performed. Release of cytokines, nitric oxide synthase production, TGF-beta, VEGF, α-smooth muscle actin, PREP, Endoglin, and IL-8 quantification were investigated. (3) Results: KYP-2047 treatment ameliorated the histological abnormalities of the venous wall, reduced the collagen increase and modulated elastin content, lowered cytokines levels and prevented mast degranulation. Moreover, a decreased expression of TGF-beta, eNOS, VEGF, α-smooth muscle actin, IL-8, and PREP was observed in in vivo study; also a reduction in VEGF and Endoglin expression was confirmed in tissue block culture study. (4) Conclusions: For the first time, this research, highlighting the importance of POP as new target for vascular disorders, revealed the therapeutic potential of KYP-2047 as a helpful treatment for the management of CVI.

scholarly journals Combination of 13-Cis Retinoic Acid and Lovastatin: Marked Antitumor Potential In Vivo in a Pheochromocytoma Allograft Model in Female Athymic Nude Mice

Endocrinology ◽  
2014 ◽  
Vol 155 (7) ◽  
pp. 2377-2390 ◽  
Author(s):  
Svenja Nölting ◽  
Alessio Giubellino ◽  
Yasin Tayem ◽  
Karen Young ◽  
Michael Lauseker ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Retinoic Acid ◽  
Smooth Muscle Actin ◽  
Treated Group ◽  
Muscle Actin ◽  
Tumor Mass ◽  
Viable Tumor ◽  
Over Time

Currently, there are no reliably effective therapeutic options for metastatic pheochromocytoma (PCC) and paraganglioma. Moreover, there are no therapies that may prevent the onset or progression of tumors in patients with succinate dehydrogenase type B mutations, which are associated with very aggressive tumors. Therefore, we tested the approved and well-tolerated drugs lovastatin and 13-cis-retinoic acid (13cRA) in vitro in an aggressive PCC mouse cell line, mouse tumor tissue-derived (MTT) cells, and in vivo in a PCC allograft nude mouse model, in therapeutically relevant doses. Treatment was started 24 hours before sc tumor cell injection and continued for 30 more days. Tumor sizes were measured from outside by caliper and sizes of viable tumor mass by bioluminescence imaging. Lovastatin showed antiproliferative effects in vitro and led to significantly smaller tumor sizes in vivo compared with vehicle treatment. 13cRA promoted tumor cell growth in vitro and led to significantly larger viable tumor mass and significantly faster increase of viable tumor mass in vivo over time compared with vehicle, lovastatin, and combination treatment. However, when combined with lovastatin, 13cRA enhanced the antiproliferative effect of lovastatin in vivo. The combination-treated mice showed slowest tumor growth of all groups with significantly slower tumor growth compared with the vehicle-treated mice and significantly smaller tumor sizes. Moreover, the combination-treated group displayed the smallest size of viable tumor mass and the slowest increase in viable tumor mass over time of all groups, with a significant difference compared with the vehicle- and 13cRA-treated group. The combination-treated tumors showed highest extent of necrosis, lowest median microvessel density and highest expression of α-smooth muscle actin. The combination of high microvessel density and low α-smooth muscle actin is a predictor of poor prognosis in other tumor entities. Therefore, this drug combination may be a well-tolerated novel therapeutic or preventive option for malignant PCC.

The correlation of in vivo burn scar contraction with the level of α-smooth muscle actin expression

Burns ◽  
2011 ◽  
Vol 37 (8) ◽  
pp. 1367-1377 ◽  
Author(s):  
Xue-Qing Wang ◽  
Olena Kravchuk ◽  
Clay Winterford ◽  
Roy M. Kimble
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Actin ◽  
Muscle Actin ◽  
Burn Scar ◽  
Actin Expression ◽  
Scar Contraction

? Isoform of smooth muscle actin is expressed in astrocytes in vitro and in vivo

1991 ◽  
Vol 28 (4) ◽  
pp. 601-606 ◽  
Author(s):  
E. Lecain ◽  
F. Alliot ◽  
M. C. Laine ◽  
B. Calas ◽  
B. Pessac
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Actin ◽  
Muscle Actin

scholarly journals The PDE1A-PKCα Signaling Pathway Is Involved in the Upregulation of α-Smooth Muscle Actin by TGF-β1 in Adventitial Fibroblasts

2010 ◽  
Vol 47 (1) ◽  
pp. 9-15 ◽  
Author(s):  
Hai-Yan Zhou ◽  
Wen-Dong Chen ◽  
Ding-Liang Zhu ◽  
Ling-Yun Wu ◽  
Jia Zhang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Signaling Pathway ◽  
Smooth Muscle Actin ◽  
Muscle Actin ◽  
Tgf Beta ◽  
Alpha Smooth Muscle Actin ◽  
Adventitial Fibroblasts ◽  
Pkc Alpha

scholarly journals Glycogen synthase kinase-3β/β-catenin signaling regulates neonatal lung mesenchymal stromal cell myofibroblastic differentiation

2012 ◽  
Vol 303 (5) ◽  
pp. L439-L448 ◽  
Author(s):  
Antonia P. Popova ◽  
J. Kelley Bentley ◽  
Anuli C. Anyanwu ◽  
Michelle N. Richardson ◽  
Marisa J. Linn ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Glycogen Synthase ◽  
Smooth Muscle Actin ◽  
Muscle Actin ◽  
Neonatal Lung ◽  
Gsk 3Β ◽  
Tgf Β1 ◽  
Myofibroblastic Differentiation

In bronchopulmonary dysplasia (BPD), alveolar septa are thickened with collagen and α-smooth muscle actin-, transforming growth factor (TGF)-β-positive myofibroblasts. We examined the biochemical mechanisms underlying myofibroblastic differentiation, focusing on the role of glycogen synthase kinase-3β (GSK-3β)/β-catenin signaling pathway. In the cytoplasm, β-catenin is phosphorylated on the NH2 terminus by constitutively active GSK-3β, favoring its degradation. Upon TGF-β stimulation, GSK-3β is phosphorylated and inactivated, allowing β-catenin to translocate to the nucleus, where it activates transcription of genes involved in myofibroblastic differentiation. We examined the role of β-catenin in TGF-β1-induced myofibroblastic differentiation of neonatal lung mesenchymal stromal cells (MSCs) isolated from tracheal aspirates of premature infants with respiratory distress. TGF-β1 increased β-catenin expression and nuclear translocation. Transduction of cells with GSK-3β S9A, a nonphosphorylatable, constitutively active mutant that favors β-catenin degradation, blocked TGF-β1-induced myofibroblastic differentiation. Furthermore, transduction of MSCs with ΔN-catenin, a truncation mutant that cannot be phosphorylated on the NH2 terminus by GSK-3β and is not degraded, was sufficient for myofibroblastic differentiation. In vivo, hyperoxic exposure of neonatal mice increases expression of β-catenin in α-smooth muscle actin-positive myofibroblasts. Similar changes were found in lungs of infants with BPD. Finally, low-passage unstimulated MSCs from infants developing BPD showed higher phospho-GSK-3β, β-catenin, and α-actin content compared with MSCs from infants not developing this disease, and phospho-GSK-3β and β-catenin each correlated with α-actin content. We conclude that phospho-GSK-3β/β-catenin signaling regulates α-smooth muscle actin expression, a marker of myofibroblast differentiation, in vitro and in vivo. This pathway appears to be activated in lung mesenchymal cells from patients with BPD.

scholarly journals The NH2-terminal peptide of α–smooth muscle actin inhibits force generation by the myofibroblast in vitro and in vivo

2002 ◽  
Vol 157 (4) ◽  
pp. 657-663 ◽  
Author(s):  
Boris Hinz ◽  
Giulio Gabbiani ◽  
Christine Chaponnier
Keyword(s):  
Smooth Muscle ◽  
Granulation Tissue ◽  
Contractile Activity ◽  
Smooth Muscle Actin ◽  
Topical Administration ◽  
Force Generation ◽  
Muscle Actin ◽  
Actin Isoforms

Myofibroblasts are specialized fibroblasts responsible for granulation tissue contraction and the soft tissue retractions occurring during fibrocontractive diseases. The marker of fibroblast-myofibroblast modulation is the neo expression of α–smooth muscle actin (α-SMA), the actin isoform typical of vascular smooth muscle cells that has been suggested to play an important role in myofibroblast force generation. Actin isoforms differ slightly in their NH2-terminal sequences; these conserved differences suggest different functions. When the NH2-terminal sequence of α-SMA Ac-EEED is delivered to cultured myofibroblast in the form of a fusion peptide (FP) with a cell penetrating sequence, it inhibits their contractile activity; moreover, upon topical administration in vivo it inhibits the contraction of rat wound granulation tissue. The NH2-terminal peptide of α–skeletal actin has no effect on myofibroblasts, whereas the NH2-terminal peptide of β–cytoplasmic actin abolishes the immunofluorescence staining for this isoform without influencing α-SMA distribution and cell contraction. The FPs represent a new tool to better understand the specific functions of actin isoforms. Our findings support the crucial role of α-SMA in wound contraction. The α-SMA–FP will be useful for the understanding of the mechanisms of connective tissue remodeling; moreover, it furnishes the basis for a cytoskeleton-dependent preventive and/or therapeutic strategy for fibrocontractive pathological situations.

scholarly journals p21waf1/cip1/sdi1 as a Central Regulator of Inducible Smooth Muscle Actin Expression and Differentiation of Cardiac Fibroblasts to Myofibroblasts

2007 ◽  
Vol 18 (12) ◽  
pp. 4837-4846 ◽  
Author(s):  
Sashwati Roy ◽  
Savita Khanna ◽  
Trenton Rink ◽  
Jared Radtke ◽  
W. Taylor Williams ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Molecular Mechanisms ◽  
Cardiac Fibroblasts ◽  
Smooth Muscle Actin ◽  
Ischemia Reperfusion ◽  
Boundary Region ◽  
Muscle Actin ◽  
Phenotypic Switch ◽  
Infarct Region

The phenotypic switch of cardiac fibroblasts (CFs) to myofibroblasts is essential for normal and pathological wound healing. Relative hyperoxic challenge during reoxygenation causes myocardial remodeling. Here, we sought to characterize the novel O2-sensitive molecular mechanisms responsible for triggering the differentiation of CFs to myofibroblasts. Exposure of CFs to hyperoxic challenge–induced transcription of smooth muscle actin (SMA) and enhanced the stability of both Acta2 transcript as well as of SMA protein. Both p21 deficiency as well as knockdown blunted hyperoxia-induced Acta2 and SMA response. Strikingly, overexpression of p21 alone markedly induced differentiation of CFs under normoxia. Overexpression of p21 alone induced SMA transcription by down-regulating YB1 and independent of TGFβ1. In vivo, hyperoxic challenge induced p21-dependent differentiation of CFs to myofibroblasts in the infarct boundary region of ischemia-reperfused heart. Tissue elements were laser-captured from infarct boundary and from a noninfarct region 0.5 mm away. Reperfusion caused marked p21 induction in the infarct region. Acta2 as well as SMA expression were markedly up-regulated in CF-rich infarct boundary region. Of note, ischemia-reperfusion–induced up-regulation of Acta2 in the infarct region was completely abrogated in p21-deficient mice. This observation establishes p21 as a central regulator of reperfusion-induced phenotypic switch of CFs to myofibroblasts.

Alpha-smooth muscle actin in pathological human disc nucleus pulposus cells in vivo and in vitro

2004 ◽  
Vol 12 (4) ◽  
pp. 430-438 ◽  
Author(s):  
Dawn Hastreiter ◽  
Jeannie Chao ◽  
QI Wang ◽  
Richard M. Ozuna ◽  
Myron Spector
Keyword(s):  
Smooth Muscle ◽  
Nucleus Pulposus ◽  
Smooth Muscle Actin ◽  
Muscle Actin ◽  
Nucleus Pulposus Cells ◽  
Alpha Smooth Muscle Actin
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