Upregulation of miR-133a by adiponectin inhibits pyroptosis pathway and rescues acute aortic dissection

2020 ◽  
Vol 52 (9) ◽  
pp. 988-997
Author(s):  
Haizhen Duan ◽  
Xiaojun Zhang ◽  
Renjie Song ◽  
Tongying Liu ◽  
Yuanyuan Zhang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Aortic Dissection ◽  
Acute Aortic Dissection ◽  
Smooth Muscle Actin ◽  
Middle Layer ◽  
Specific Protein ◽  
Receptor Protein ◽  
Mice Model

Abstract Acute aortic dissection (AAD) is a cardiovascular emergency caused by the formation of hematoma in the middle layer of the aortic wall. Adiponectin (APN) is an adipose tissue-specific protein that has anti-inflammation and anti-atherosclerosis functions. Pyroptosis, as an inflammatory cell death, depends on the activation of caspase1, while nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) is a typical representative of the pyroptosis pathway. In this study, we aimed to find whether APN affects the AAD process. The results showed that APN overexpression (OE) inhibited the AAD development and the levels of glucose, triglyceride, and total cholesterol in mice model. In addition, APN OE inhibited the productions of gasdermin D (GSDMD), NLRP3, caspase1, interleukin-1β (IL-1β), IL-18, and osteopontin (OPN), as well as α-smooth muscle actin (α-SMA) downregulation in vitro and in vivo. In addition, NLRP3 was found to be a target gene of miR-133a and miR-133a OE showed similar effects to APN OE in attenuating the LPS-induced productions of GSDMD, NLRP3, caspase1, IL-1β, IL-18, and OPN, as well as α-SMA downregulation in vascular smooth muscle cells (vSMCs). Moreover, the beneficial effects of APN OE were abolished by miR-133a knockdown in vSMCs. In conclusion, our present results indicated that the upregulation of miR-133a by APN inhibits pyroptosis pathway, which potentially rescues AAD.

scholarly journals Ursodeoxycholic Acid Attenuates Acute Aortic Dissection Formation in Angiotensin II-Infused Apolipoprotein E-Deficient Mice Associated with Reduced ROS and Increased Nrf2 Levels

2016 ◽  
Vol 38 (4) ◽  
pp. 1391-1405 ◽  
Author(s):  
Wanjun Liu ◽  
Bei Wang ◽  
Tao Wang ◽  
Xintian Liu ◽  
Xingwei He ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Aortic Dissection ◽  
Ursodeoxycholic Acid ◽  
Acute Aortic Dissection ◽  
Dependent Manner ◽  
Ang Ii

Background/Aims: Acute aortic dissection (AAD) is characterized by excessive smooth muscle cell (SMC) loss, extracellular matrix (ECM) degradation and inflammation. In response to certain stimulations, oxidative stress is activated and regulates apoptosis and inflammation. Excessive apoptosis promotes aortic inflammation and degeneration, leading to AAD formation. This study aimed to clarify role of oxidative stress in the pathogenesis of AAD and whether the antioxidant ursodeoxycholic acid (UDCA) attenuates AAD formation. Methods: Angiotensin II (Ang II) was infused in 8-months male ApoE-/- mice for one week to establish a model of AAD. UDCA (10 mg/kg/day) was administered via intragastric gavage for 3 consecutive days before AngII infusion and also during the AngII infusion for another consecutive 7 days. Results: Ang II-infusion resulted in the incidence of AAD at a rate of 35% (13/37) and UDCA markedly reduced the incidence of AAD to 16% (6/37), accompanied with reduced maximal aortic diameter measured at the suprarenal region of the abdominal aorta. Additionally, UDCA pretreatment prevented Ang II induced generations of reactive oxygen species (ROS) and apoptosis of vascular smooth muscle cells (VSMCs) both in vivo and in. vitro Mechanistically, we found UDCA markedly increased Nrf2 expression in VSMCs and prevented Ang II induced expression of NADPH subunits (p47, p67 and gp91) in Nrf2-dependent manner and rescued the activity of redox enzymes (Cu/Zn-SOD, Mn-SOD and CAT), thereby inhibiting apoptosis of VSMCs. Conclusion: These results demonstrate that UDCA prevented AAD formation by reducing apoptosis of VSMCs caused by oxidative stress in Nrf2 dependent manner and suggest that UDCA might have clinical potential to suppress AAD formation.

Abstract 38: Rbp-j Regulates the Genetic Program of the Myo-epithelioid JG Cell

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Ruth M Castellanos Rivera ◽  
Ellen S. Pentz ◽  
Kenneth W. Gross ◽  
Silvia Medrano ◽  
Jing Yu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Fluorescent Protein ◽  
Smooth Muscle Actin ◽  
Artificial Chromosome ◽  
Specific Protein ◽  
Genetic Program ◽  
Cell Phenotype ◽  
Gfp Expression ◽  
Renin Gene

RBP-J , the major downstream effector of Notch signaling, is necessary to maintain the number of juxtaglomerular (JG) cells. In addition, RBP-J regulates the plasticity of arteriolar smooth muscle cells to adopt the renin cell phenotype when homeostasis is threatened. We hypothesized that RBP-J acts as an on/off switch controlling the expression of genes that determine the renin phenotype. To determine whether RBP-J directly affects renin gene expression, we generated mice harboring a bacterial artificial chromosome (BAC) transgene with green fluorescent protein (GFP) under the control of the renin gene carrying a mutation in its RBP-J- binding site (Mut-BAC). Mut-BAC mice had markedly reduced GFP expression to 12.9 % ±0.01 (n=3) of the control (Wt-BAC) and a diminished response to homeostatic challenges: mut-BAC mice had a reduced number of GFP positive JG areas per total number of glomeruli (Wt-BAC: 25.1 % ±3.0, n=3; Mut-BAC: 9.3 % ±1.4, n=2, p<0.02) and no GFP expression along the arterioles. To determine whether the decrease in the number of JG cells in mice lacking RBP-J (cKO) was due to a diminished endowment of renin progenitor cells, we traced the fate of cells derived from the renin lineage by generating mice ( RBP-J fl/fl ; Ren1d +/cre ; R26R +/- ) in which cells lacking RBP-J simultaneously expressed β-galactosidase (β-gal). The pattern of β-gal in cKO and control kidneys was identical, indicating that cells derived from the renin lineage did not die but instead changed their phenotype. Next we investigated the phenotype adopted by the cells derived from the renin lineage. Expression of α-smooth muscle actin and smoothelin (a marker of mature smooth muscle) was significantly decreased to 41 % ±7.0 (n=2) and 44 % ±8.8 (n=2) respectively with respect to controls (p<0.01). In addition, mutant JG cells in vivo did not express genes characteristic of the renin phenotype such as renin, calponin1, Nfat and Akr1b7 expressing instead fibroblast-specific protein 1 indicating the adoption of a fibroblast-like phenotype. Results indicate that RBP-J directly governs a genetic program that controls the dual endocrine-contractile phenotype of the JG cell, which is crucial to maintain blood pressure and fluid-electrolyte homeostasis.

Abstract 064: The Lipoxigenase Inhibitor Nordihydroguaiaretic Acid Prevents the Development of Hypoxia-Induced Pulmonary Hypertension in Mice

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Andrea Iorga ◽  
Gabriel Wong ◽  
Denise Mai ◽  
Jingyuan Li ◽  
Salil Sharma ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Smooth Muscle Actin ◽  
Nordihydroguaiaretic Acid ◽  
Treated Group ◽  
Oxidation Products ◽  
Lipoxygenase Inhibitor ◽  
Human Pulmonary Artery

Pulmonary hypertension (PH) is a chronic lung disease characterized by progressively elevated pulmonary arterial pressures and severe pulmonary vascular remodeling resulting from interactions between oxidized lipoprotein deposition and increased endothelial proliferation. Previously we have shown increased plasma levels of biological oxidation products such as hydroxyoctadecadienoic acids (HODEs) and hydroxyeicosatetraenoic acids (HETEs) in the rat monocrotaline model of PH. Here we investigated the role of HETEs and HODEs in the development of PH and whether their inhibition with the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) attenuates the progression of PH. Mice were placed in a hypoxic chamber with O2 concentrations of ≤10% for 21 days and either left untreated to develop PH (n=7) or treated with NDGA daily (10mg/kg/day, i.p., n=4) from day 1. Direct RV catheterization was terminally performed to record RV pressure (RVP). Pulmonary arteriolar thickening and oxidized lipid deposition were assessed by staining lung sections with Masson’s Trichrome or with α-smooth muscle actin and E-06 (marker for oxidized low-density lipoproteins). In vitro, human pulmonary artery smooth muscle cell (hPASMC) proliferation was assessed by MTT assays in the absence or presence of 12-HETE (100ng/ml), 9-HODE (1µg/ml) and 13-HODE (1µg/ml) alone or together with NDGA (10, 25 and 50µM). In-vitro, HETE/HODE treatment increased hPASMC proliferation ~ 2-fold when compared to untreated cells and NDGA significantly inhibited the proliferative effects of all three oxidized lipids. In-vivo, NDGA treatment prevented the development of PH. RVP was lower in the NDGA-treated group vs. the PH group (24.01±1.39mmHg vs. 36.91±5.74mmHg, p<0.05) and was comparable to control normoxic mice (20.93±2.52mmHg). RV hypertrophy index was significantly elevated in the PH mice versus control mice (0.38±0.03 vs. 0.28±0.02 (p<0.001), while NDGA treatment completely prevented the development of RV hypertrophy (0.28±0.04). Lung sections demonstrated arteriolar thickening and E-06 positive deposits in the PH group, which was prevented by NDGA therapy. We conclude that oxidized fatty acid deposition and accumulation might play a role in the development of PH.

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.

? 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 Protective Effect of Salidroside on Hypoxia-Induced Corpus Cavernosum Smooth Muscle Cell Phenotypic Transformation

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Xiang Zhang ◽  
Jian-feng Zhao ◽  
Fan Zhao ◽  
Jun-feng Yan ◽  
Fan Yang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Actin ◽  
Hypoxia Inducible Factor ◽  
Corpus Cavernosum ◽  
Treatment Method ◽  
Synthetic Protein ◽  
Phenotypic Transformation ◽  
New Treatment

Salidroside, a major active ingredient isolated from Rhodiola rosea, has a long application in Chinese medical history. It has widely demonstrated effects on fatigue, psychological stress, and depression and exhibits potential antihypoxia activity. Emerging evidence shows that hypoxia is an important independent risk factor for erectile dysfunction (ED). The aim of this study was to clarify the effect of salidroside on hypoxia-induced phenotypic transformation of corpus cavernosum smooth muscle cells (CCSMCs). Our results showed that salidroside decreased the hypoxia-induced expression of collagen and content of vimentin, a corpus cavernosum smooth muscle synthetic protein, in vitro. Simultaneously, salidroside increased expression of the CCSMC contractile proteins, α-smooth muscle actin (α-SMA) and desmin. In vivo, similarly, the expressions of collagen and hypoxia-inducible factor-1α were increased in bilateral cavernous neurectomy (BCN) rats while they were decreased in the salidroside group. Among the phenotypic proteins, α-SMA and desmin increased and vimentin decreased after treating BCN rats with salidroside compared with the BCN alone group. Overall, our results demonstrate that salidroside has the ability to oppose hypoxia and can inhibit the CCSMC phenotypic transformation induced by hypoxia. Salidroside may provide a new treatment method for ED.

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.

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

scholarly journals The specific NH2-terminal sequence Ac-EEED of alpha-smooth muscle actin plays a role in polymerization in vitro and in vivo.

1995 ◽  
Vol 130 (4) ◽  
pp. 887-895 ◽  
Author(s):  
C Chaponnier ◽  
M Goethals ◽  
P A Janmey ◽  
F Gabbiani ◽  
G Gabbiani ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Actin Polymerization ◽  
Smooth Muscle Actin ◽  
Muscle Actin ◽  
Alpha Smooth Muscle Actin ◽  
Fab Fragment ◽  
Acetyl Group ◽  
Antibody Complex

The blocking effect of the NH2-terminal decapeptide of alpha-smooth muscle (SM) actin AcEEED-STALVC on the binding of the specific monoclonal antibody anti-alpha SM-1 (Skalli, O., P. Ropraz, A. Trzeviak, G. Benzonana, D. Gillessen, and G. Gabbiani. 1986. J. Cell Biol. 103:2787-2796) was compared with that of synthetic peptides modified by changing the acetyl group or by substituting an amino acid in positions 1 to 5. Using immunofluorescence and immunoblotting techniques, anti-alpha SM-1 binding was abolished by the native peptide and by peptides with a substitution in position 5, indicating that AcEEED is the epitope for anti-alpha SM-1. Incubation of anti-alpha SM-1 (or of its Fab fragment) with arterial SM actin increased polymerization in physiological salt conditions; the antibody binding did not hinder the incorporation of the actin antibody complex into the filaments. This action was not exerted on skeletal muscle actin. After microinjection of the alpha-SM actin NH2-terminal decapeptide or of the epitopic peptide into cultured aortic smooth muscle cells, double immunofluorescence for alpha-SM actin and total actin showed a selective disappearance of alpha-SM actin staining, detectable at approximately 30 min. When a control peptide (e.g. alpha-skeletal [SK] actin NH2-terminal peptide) was microinjected, this was not seen. This effect is compatible with the possibility that the epitopic peptide traps a protein involved in alpha-SM actin polymerization during the dynamic filament turnover in stress fibers. Whatever the mechanism, this is the first evidence that the NH2 terminus of an actin isoform plays a role in the regulation of polymerization in vitro and in vivo.

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