scholarly journals MicroRNA-145 Involves in the Pathogenesis of Renal Vascular Lesions and May Become a Potential Therapeutic Target in Patients with Juvenile Lupus Nephritis

2019 ◽  
Vol 44 (4) ◽  
pp. 643-655 ◽  
Author(s):  
Zhaomin Cai ◽  
Wei Xiang ◽  
Xiaojie Peng ◽  
Yan Ding ◽  
Wang Liao ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Lupus Nephritis ◽  
Smooth Muscle Actin ◽  
Vascular Lesions ◽  
Alpha Smooth Muscle Actin ◽  
Migration Ability ◽  
Phenotypic Transformation ◽  
And Migration ◽  
Renal Vascular ◽  
Proliferation And Migration

Aims: The current study was conducted with the central objective of investigating the expression of microRNA-145 (miR-145) in renal vascular lesions (RVLs) in juvenile lupus nephritis (JLN) and its possible mechanism. Methods: The clinical data of 49 JLN patients confirmed by renal biopsy were collected and followed by grouping according to the RVLs score after hematoxylin-eosin staining: mild, moderate, and severe groups. In situ hybridization was used to detect the expression of miR-145 in renal vessels which was then being compared among different RVLs groups. Up-LV-miR-145 and LV-miR-NC lentiviral vectors were constructed and transfected into human vascular smooth muscle cells (HVSMCs), respectively. After HVSMCs were treated with 10.0 µg/L platelet-derived growth factor (PDGF)-BB for 24 h, the proliferation, migration, and apoptosis of endothelial cells were detected by MTT, Transwell assay, and flow cytometry, respectively. Western blot was used to detect expression of alpha-smooth muscle actin (α-SM-actin) and osteopontin (OPN). Results: The expression of miR-145 in renal vascular cells was statistically significant. The higher the inner membrane ratio, the lesser the miR-145 expression. After treatment with PDGF-BB, expression of miR-145 in HVSMCs decreased, proliferation and migration ability enhanced, apoptosis decreased, α-SM-actin decreased, and OPN increased. The proliferation and migration ability of HVSMCs in the LV-miR-145 group suppressed, apoptosis enhanced, α-SM-actin increased, and OPN decreased. Conclusions: Our study revealed that miR-145 expression decreased with the increase of vascular damage. miR-145 can inhibit proliferation, migration, and differentiation phenotypic transformation of HVSMCs induced by PDGF-BB. miR-145 may be involved in the pathogenesis of RVLs and may be a new target for treatment of RVLs in lupus nephritis.

scholarly journals MiR-18a Inhibits PI3K/AKT Signaling Pathway to Regulate PDGF BB-Induced Airway Smooth Muscle Cell Proliferation and Phenotypic Transformation

2021 ◽  
pp. 883-892
Author(s):  
W. Yang ◽  
Y. Chen ◽  
C. Huang ◽  
W. Wang ◽  
C. Huang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Airway Remodeling ◽  
Akt Pathway ◽  
Airway Smooth Muscle Cells ◽  
Migration Ability ◽  
Phenotypic Transformation ◽  
And Migration ◽  
Proliferation And Migration

The increased proliferation and migration of airway smooth muscle cells (ASMCs) is a key process in the formation of airway remodeling in asthma. In this study, we focused on the expression of mircoRNA-18a (miR-18a) in airway remodeling in bronchial asthma and its related mechanisms. ASMCs are induced by platelet-derived growth factor BB (PDGF-BB) for in vitro airway remodeling. The expression of miR-18a in sputum of asthmatic patients and healthy volunteers was detected by qRT-PCR. The expression of miR-18a was over-expressed or interfered with in PDGF-BB-treated ASMCs. Cell proliferation, apoptosis and migration were detected by MTT, flow cytometry and Transwell, respectively; the expression of contractile phenotype marker proteins (SM-22α, α-SM-actin, calponin) and key molecules of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway (PI3K, p-PI3K, AKT and p-AKT) in ASMCs were detected by Western blot. The expression of miR-18a was down-regulated in the sputum and PDGF-BB-treated ASMCs of asthma patients. PDGF-BB could promote the proliferation and migration of ASMCs and inhibit their apoptosis; it could also promote the phenotypic transformation of ASMCs and activate the PI3K/AKT pathway. MiR-18a could inhibit the proliferation, migration ability and phenotypic transformation of ASMCs induced by PDGF-BB to a certain extent and alleviate the effect of PDGF-BB in supressing apoptosis, while miR-18a could inhibit the activation of the PI3K/AKT pathway. MiR-18a inhibits PDGF-BB-induced proliferation, migration and phenotypic conversion of ASMCs by inhibiting the PI3K/AKT pathway, thus attenuating airway remodeling in asthma.

scholarly journals Metformin attenuates carotid neointimal hyperplasia by modulating the vascular smooth muscle cell phenotype transformation through upregulation of TET2, Nur77 and calponin

2021 ◽  
Vol 73 (1) ◽  
pp. 135-144
Author(s):  
Hao Lin ◽  
Shuo Cheng ◽  
Zhichao Yuan ◽  
Zhiqiang Yan ◽  
Jifa Zhang
Keyword(s):  
Smooth Muscle ◽  
Carotid Artery ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Actin ◽  
Neointimal Hyperplasia ◽  
Nuclear Antigen ◽  
Cell Phenotype ◽  
Alpha Smooth Muscle Actin ◽  
And Migration ◽  
Proliferation And Migration

Metformin is a drug used to treat type 2 diabetes based on its effectiveness as well as cardiovascular safety. Metformin has been shown to modulate proliferation and migration of vascular smooth muscle cells (VSMCs), but the underlying mechanisms of the effect of metformin on VSMC function remains unclear. We found that metformin inhibits VSMC proliferation and migration and upregulates the expression of nuclear receptor subfamily 4 group A member 1 (Nur77), ten-eleven translocation 2 (TET2), and calponin in vitro. In the carotid artery balloon injury model of rats, metformin effectively prevented neointimal hyperplasia in the carotid artery, including neointimal thickness, increased neointimal area, and the neointimal area/medial area ratio. It also reduced the number of proliferating cell nuclear antigen (PCNA)+ cells and increased the expression of Nur77, calponin and alpha-smooth muscle actin (?-SMA). These results show that metformin attenuates neointimal hyperplasia in balloon-injured carotid arteries via increased expression of TET2, Nur77 and calponin, and reduced expression of matrix metallopeptidase 9 (MMP-9).

Isoliquiritigenin inhibits TGF-β1-induced fibrogenesis through activating autophagy via PI3K/AKT/mTOR pathway in MRC-5 cells

2020 ◽  
Vol 52 (8) ◽  
pp. 810-820 ◽  
Author(s):  
Jinjuan He ◽  
Hao Peng ◽  
Meifang Wang ◽  
Ying Liu ◽  
Xingrong Guo ◽  
...  
Keyword(s):  
Antioxidant Activities ◽  
Smooth Muscle Actin ◽  
Mtor Pathway ◽  
Type I ◽  
Akt Inhibitor ◽  
Alpha Smooth Muscle Actin ◽  
Human Lung Fibroblast ◽  
And Migration ◽  
Tgf Β1 ◽  
Proliferation And Migration

Abstract Isoliquiritigenin (ISL), a natural flavonoid derived from the root of liquorice, has been reported to possess anti-inflammatory and antioxidant activities. Previous studies have found that ISL plays a crucial role in anti-fibrosis of adipose tissue and renal tissue; however, its effect on pulmonary fibrogenesis has not been demonstrated. In this study, we aimed to explore the roles and the underlying mechanisms of ISL in TGF-β1-induced fibrogenesis using human lung fibroblast-derived MRC-5 cells. Cell proliferation and migration were determined by MTT and wound healing assay, respectively. The expression levels of alpha-smooth muscle actin (α-SMA), collagen type I alpha 1 (COLIA1) and fibronectin (FN), microtubule-associated protein light chain 3 (LC3) and related signaling molecules were detected by quantitative real-time PCR, western blot and immunofluorescence assay, correspondingly. EGFP-LC3 transfection was used for autophagy analysis. The results showed that ISL inhibited the TGF-β1-induced proliferation and migration, and down-regulated the expressions of α-SMA, COLIA1 and FN. ISL treatment led to up-regulation of LC3 in TGF-β1-treated MRC-5 cells, accompanied by significant decrease in the phosphorylation levels of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR). In addition, the inhibitory effects of ISL on TGF-β1-induced fibrogenic features in MRC-5 cells were enhanced by pretreatment with autophagy activator Rapmycin and PI3K/AKT inhibitor LY294002 and reversed by autophagy inhibitor 3-methyladenine and PI3K/AKT activator IGF-1. Taken together, our results demonstrated that ISL could attenuate the fibrogenesis of TGF-β1-treated MRC-5 cells by activating autophagy via suppressing the PI3K/AKT/mTOR pathway. Therefore, ISL holds a great potential to be developed as a novel therapeutic agent for the treatment of pulmonary fibrosis.

scholarly journals Cathelicidin Modulates Vascular Smooth Muscle Cell Phenotypic Switching through ROS/IL-6 Pathway

Antioxidants ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 491
Author(s):  
Xiaoliang Dong ◽  
Di Wu ◽  
Yihan Zhang ◽  
Lingling Jia ◽  
Xiaohua Pan ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Actin ◽  
Nuclear Factor Κb ◽  
Janus Kinase ◽  
Phenotypic Switching ◽  
Phenotypic Transformation ◽  
Underlying Mechanisms ◽  
And Migration ◽  
Relationship Of

Vascular smooth muscle cells (VSMC) are stromal cells of the blood vessels and their differentiation is thought to be essential during atherosclerosis. Cathelicidin-related antimicrobial peptides (CRAMP) are suggested to play a role in the development of atherosclerosis. Even so, the relationship of CRAMP and VSMC remains unclear. The present study was to determine whether CRAMP regulates VSMC phenotypic transformation and underlying mechanisms. We demonstrated that CRAMP could reverse platelet-derived growth factor-BB (PDGF-BB)-induced VSMC phenotypic transformation, evidencing by increasing α-smooth muscle actin (α-SMA), smooth muscle 22α (SM22α) and decreasing of proliferation and migration. Further studies showed that CRAMP inhibited nuclear factor κB (NF-κB)-induced autocrine of interleukin-6 (IL-6), which further activated of janus kinase 2 (JAK2)/signal transducer and activator 3 (STAT3). Meanwhile, our data showed that CRAMP can significantly inhibit PDGF-BB enhanced intracellular reactive oxygen species (ROS) level which further affected the NF-κB signaling pathway, indicating that CRAMP can regulate the phenotypic transformation of VSMC by regulating oxidative stress. These results indicated that CRAMP regulated the differentiation of VSMC by inhibiting ROS-mediated IL-6 autocrine, suggesting that targeting CRAMP is a potential avenue for regulating the differentiation of VSMC and treatment of atherosclerosis.

Abstract 311: TGFb/Smad3 Stimulation Drives Smooth Muscle Cell De-differentiation

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Daniel M DiRenzo ◽  
Xudong Shi ◽  
Stephen Seedial ◽  
Lian-wang Guo ◽  
Bo Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Balloon Angioplasty ◽  
Intimal Hyperplasia ◽  
Cellular Proliferation ◽  
Smooth Muscle Actin ◽  
Tgfβ Signaling ◽  
And Migration ◽  
Proliferation And Migration

Restenosis, or vessel re-narrowing, occurs in approximately 25-50% of arterial interventions involving balloon angioplasty due to the formation of a proliferative plaque in the vessel lumen termed neo-intimal hyperplasia. Arterial smooth muscle cells (SMCs) contribute to neo-intimal hyperplasia through a de-differentiation process that includes downregulation of their contractile gene expression and conversion to a phenotype that includes proliferation, migration, and matrix synthesis. Expression of TGFβ and its downstream signaling protein, Smad3, are greatly upregulated following vascular injury, including balloon angioplasty. Classically, TGFβ signaling has been shown to suppress SMC proliferation and migration in vitro, however, Smad3 overexpressing SMCs demonstrate enhanced proliferation and migration. Furthermore, overexpression of Smad3 in rat carotid arteries enhances neo-intimal hyperplasia following balloon angioplasty. These results lead us to hypothesize that TGFβ signaling, in the context of upregulated Smad3, drives SMC de-differentiation leading to enhanced cellular proliferation and migration. We utilized primary rat SMCs infected with adenovirus constructs overexpressing Smad3 or GFP control and performed gene expression microarrays 24 hours following TGFβ administration. We observed statistically significant (p<0.05) upregulation of 145 genes and downregulation of 76 genes by more than 3-fold. GO term analysis revealed that genes involved in embryonic tissue development (41 genes) and stem/progenitor cell differentiation (27 genes) were significantly enriched in TGFβ/Smad3 stimulated cells. Confirmatory qRT-PCR demonstrated that the contractile genes SM-MHC, smooth muscle actin, and calponin were significantly downregulated -6.3, -2.7 and -2.1 fold, respectively. In contrast, stem/developmental related genes Cxcr4, Cd34, Wnt11, Wnt2b and IL11 were significantly upregulated by 105.2, 22.3, 11.5, 14.0, and 12.5 fold, respectively. These results strongly suggest that TGFβ/Smad3 stimulation is a powerful de-differentiation signal in SMCs and plays an important role in the development of neo-intimal hyperplasia.

scholarly journals Myristoylation of LMCD1 Leads to Its Species-Specific Derepression of E2F1 and NFATc1 in the Modulation of CDC6 and IL-33 Expression During Development of Vascular Lesions

2020 ◽  
Vol 40 (5) ◽  
pp. 1256-1274
Author(s):  
Suresh Govatati ◽  
Prahalathan Pichavaram ◽  
Jagadeesh Janjanam ◽  
Liang Guo ◽  
Renu Virmani ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Specific Role ◽  
Vascular Lesions ◽  
Aortic Smooth Muscle Cells ◽  
Aortic Smooth Muscle ◽  
And Migration ◽  
Species Specific ◽  
Proliferation And Migration

Objective: In view of our previous observations on differential expression of LMCD1 (LIM and cysteine-rich domains 1) in human versus rodents, we asked the question whether LMCD1 plays a species-specific role in the development of vascular lesions. Approach and Results: A combination of genetic, molecular, cellular, and disease models were used to test species-specific role of LMCD1 in the pathogenesis of vascular lesions. Here, we report species-specific regulation of LMCD1 expression in mediating vascular smooth muscle cell proliferation and migration during vascular wall remodeling in humans versus mice. Thrombin induced LMCD1 expression in human aortic smooth muscle cells but not mouse aortic smooth muscle cells via activation of Par1 (protease-activated receptor 1)-Gαq/11 (Gα protein q/11)-PLCβ3 (phospholipase Cβ3)-NFATc1 (nuclear factor of activated T cells 1) signaling. Furthermore, although LMCD1 mediates thrombin-induced proliferation and migration of both human aortic smooth muscle cells and mouse aortic smooth muscle cells via influencing E2F1 (E2F transcription factor 1)-mediated CDC6 (cell division cycle 6) expression and NFATc1-mediated IL (interleukin)-33 expression, respectively, in humans, it acts as an activator, and in mice, it acts as a repressor of these transcriptional factors. Interestingly, LMCD1 repressor activity was nullified by N-myristoyltransferase 2–mediated myristoylation in mouse. Besides, we found increased expression of LMCD1 in human stenotic arteries as compared to nonstenotic arteries. On the other hand, LMCD1 expression was decreased in neointimal lesions of mouse injured arteries as compared to noninjured arteries. Conclusions: Together, these observations reveal that LMCD1 acts as an activator and repressor of E2F1 and NFATc1 in humans and mice, respectively, in the induction of CDC6 and IL-33 expression during development of vascular lesions. Based on these findings, LMCD could be a potential target for drug development against restenosis and atherosclerosis in humans.

scholarly journals Attenuation of proliferation and migration of retinal pericytes in the absence of thrombospondin-1

2009 ◽  
Vol 296 (4) ◽  
pp. C724-C734 ◽  
Author(s):  
Elizabeth A. Scheef ◽  
Christine M. Sorenson ◽  
Nader Sheibani
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Actin ◽  
Significant Loss ◽  
Matricellular Protein ◽  
Stem Cell Markers ◽  
Vsmc Proliferation ◽  
Retinal Pericytes ◽  
And Migration ◽  
First Time ◽  
Proliferation And Migration

Perivascular supporting cells, including vascular smooth muscle cells (VSMCs) and pericytes (PCs), provide instructive signals to adjacent endothelial cells helping to maintain vascular homeostasis. These signals are provided through direct contact and by the release of soluble factors by these cells. Thrombospondin (TSP)1 is a matricellular protein and an autocrine factor for VSMCs. TSP1 activity, along with that of PDGF, regulates VSMC proliferation and migration. However, the manner in which TSP1 and PDGF impact retinal PC function requires further investigation. In the present study, we describe, for the first time, the isolation and culture of retinal PCs from wild-type (TSP1+/+) and TSP1-deficient (TSP1−/−) immortomice. We showed that these cells express early and mature markers of PCs, including NG2, PDGF receptor-β, and smooth muscle actin as well as desmin, calbindin, and mesenchymal stem cell markers. These cells were successfully passaged and maintained in culture for several months without significant loss of expression of these markers. TSP1+/+ PCs proliferated at a faster rate compared with TSP1−/− PCs. In addition, TSP1+/+ PCs, like VSMCs, responded to PDGF-BB with enhanced migration and proliferation. In contrast, TSP1−/− PCs failed to respond to the promigratory and proliferative activity of PDGF-BB. This may be attributed, at least in part, to the limited interaction of PDGF-BB with TSP1 in null cells, which is essential for PDGF proliferative and migratory action. We observed no significant differences in the rates of apoptosis in these cells. TSP1−/− PCs were also less adherent, expressed increased levels of TSP2 and fibronectin, and had decreased amounts of N-cadherin and αvβ3-integrin on their surface. Thus, TSP1 plays a significant role in retinal PC proliferation and migration impacting retinal vascular development and homeostasis.

scholarly journals Galectin-1 inhibits PDGF-BB-induced proliferation and migration of airway smooth muscle cells through the inactivation of PI3K/Akt signaling pathway

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Xinfeng Pang ◽  
Jing Qiao
Keyword(s):  
Smooth Muscle ◽  
Signaling Pathway ◽  
Airway Smooth Muscle ◽  
Smooth Muscle Actin ◽  
Akt Signaling ◽  
Airway Smooth Muscle Cells ◽  
Akt Signaling Pathway ◽  
Phenotype Switching ◽  
And Migration ◽  
Proliferation And Migration

Abstract Childhood asthma is one of the most common chronic childhood diseases. Platelet-derived growth factor BB (PDGF-BB) induced airway smooth muscle cell (ASMC) proliferation and migration are involved in the pathogenesis of asthma. Galectin-1 (Gal-1) is a glycan-binding protein that has been found to be involved in the progression of asthma. However, the mechanism remains unclear. In the current study, we aimed to evaluate the role of Gal-1 in regulating the phenotype switching of ASMCs, which is an important mechanism in the pathogenesis of asthma. Our results showed that Gal-1 was markedly down-regulated in the samples from asthma patients. In vitro study also proved that Gal-1 expression was decreased in PDGF-BB-stimulated ASMCs. In addition, Gal-1 overexpression significantly inhibited PDGF-BB-induced ASMCs proliferation and migration, while Gal-1 knockdown exhibits opposite effects of Gal-1 overexpression. The PDGF-BB-caused reductions in expressions of α-smooth muscle actin (α-SMA), specific muscle myosin heavy chain (SM-MHC), and calponin were elevated by Gal-1 overexpression, but were deteriorated by Gal-1 knockdown in ASMCs. Furthermore, overexpression of Gal-1 inhibited PDGF-BB-stimulated PI3K/Akt activation in ASMCs. Notably, treatment with IGF-1, an activator of PI3K, reversed the effects of Gal-1 on ASMCs proliferation, migration, and phenotype switching. In conclusion, these findings showed that Gal-1 exerted inhibitory effects on PDGF-BB-stimulated proliferation, migration, and phenotype switching of ASMCs via inhibiting the PI3K/Akt signaling pathway. Thus, Gal-1 might be a promising target for the treatment of asthma.

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