Smooth Muscle-Alpha Actin Inhibits Vascular Smooth Muscle Cell Proliferation and Migration by Inhibiting Rac1 Activity

Chen, Lihua; DeWispelaere, Allison; Dastvan, Frank; Osborne, William; Blechner, Christine; Windhorst, Sabine; Daum, Guenter

doi:10.1371/journal.pone.0155726

Cited by 23 publications

(22 citation statements)

References 31 publications

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“…In vivo, vascular smooth muscle hyperplasia in response to carotid artery injury greatly exceeded wild-type in Acta2 −/− mice (30). These and other results implicate SM α-actin in the inhibition of proliferation (31). The present observations align with the hypothesis that R258C SM α-actin disrupts an inhibitory effect of wild-type SM α-actin on proliferation, permitting hyperplastic vascular occlusions, leading to stroke (16).…”

Section: Discussionsupporting

confidence: 91%

“…It is likely that SM α-actin stabilization of stress fibers and FAs retards cell migration. By varying SM α-actin content through different approaches, several laboratories have correlated increased α-actin with inhibition of fibroblast migration (31,42,43). We confirmed such an effect on induction of SM α-actin in control cells in both the scratch and Transwell migration assays.…”

Section: Discussionsupporting

confidence: 76%

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Vascular disease-causing mutation, smooth muscle α-actin R258C, dominantly suppresses functions of α-actin in human patient fibroblasts

Liu

Chang

Grinnell

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The most common genetic alterations for familial thoracic aortic aneurysms and dissections (TAAD) are missense mutations in vascular smooth muscle (SM) α-actin encoded by ACTA2. We focus here on ACTA2-R258C, a recurrent mutation associated with early onset of TAAD and occlusive moyamoya-like cerebrovascular disease. Recent biochemical results with SM α-actin-R258C predicted that this variant will compromise multiple actin-dependent functions in intact cells and tissues, but a model system to measure R258C-induced effects was lacking. We describe the development of an approach to interrogate functional consequences of actin mutations in affected patient-derived cells. Primary dermal fibroblasts from R258C patients exhibited increased proliferative capacity compared with controls, consistent with inhibition of growth suppression attributed to SM α-actin. Telomeraseimmortalized lines of control and R258C human dermal fibroblasts were established and SM α-actin expression induced with adenovirus encoding myocardin-related transcription factor A, a potent coactivator of ACTA2. Two-dimensional Western blotting confirmed induction of both wild-type and mutant SM α-actin in heterozygous ACTA2-R258C cells. Expression of mutant SM α-actin in heterozygous ACTA2-R258C fibroblasts abrogated the significant effects of SM α-actin induction on formation of stress fibers and focal adhesions, filamentous to soluble actin ratio, matrix contraction, and cell migration. These results demonstrate that R258C dominantly disrupts cytoskeletal functions attributed to SM α-actin in fibroblasts and are consistent with deficiencies in multiple cytoskeletal functions. Thus, cellular defects due to this ACTA2 mutation in both aortic smooth muscle cells and adventitial fibroblasts may contribute to development of TAAD and proliferative occlusive vascular disease.thoracic aortic aneurysms | ACTA2 mutation | vascular disease | cell migration | human fibroblasts

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 76%

Vascular disease-causing mutation, smooth muscle α-actin R258C, dominantly suppresses functions of α-actin in human patient fibroblasts

Liu

Chang

Grinnell

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…RAC1 is involved in the modulation of phagocytosis, adhesion, cell movement, cell proliferation and axon formation ( 36 – 39 ). RAC1 serves a pivotal role in cancer angiogenesis, invasion and metastasis ( 40 , 41 ). There are ongoing in-depth studies on lung cancer clinical treatment using RAC1 as the target ( 39 , 42 ).…”

Section: Discussionmentioning

confidence: 99%

The expression of HOXA13 in lung adenocarcinoma and its clinical significance: A study based on The Cancer Genome Atlas, Oncomine and reverse transcription‑quantitative polymerase chain reaction

Deng

Zhang

et al. 2018

Oncol Lett

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Previous studies have investigated the association between HOXA13 and non-small cell lung cancer. However, the role of HOXA13 expression in the occurrence and progression of lung adenocarcinoma (LUAD) has not yet been investigated. In the present study, HOXA13-related data mining of The Cancer Genome Atlas (TCGA), polymerase chain reaction (PCR) data from our cases and the case information in Oncomine was conducted for validation. The expression data of HOXA13 in lung cancer cell lines were also collected from the Cancer Cell Line Encyclopedia (CCLE) database for further verification. A comprehensive meta-analysis of the expression of HOXA13 was also performed, integrating the data of TCGA, in-house PCR and Oncomine. Genes that were co-expressed with HOXA13 were subsequently identified through cBioPortal and Multi Experiment Matrix (MEM), and the potential role and mechanism of HOXA13 in LUAD was investigated. The expression value of HOXA13 in the LUAD group, which comprised 237 cases, was 3.74±2.694, significantly higher than its expression value in the non-cancerous group (0.92±0.608, P<0.001). The pooled SMD for HOXA13 was 0.346 (95% CI, 0.052–0.640; P=0.068; I2=51.3%; P=0.021), The meta-analysis of diagnostic tests revealed that the area under the summary receiver operating characteristic curve (SROC) was 0.78 (95% CI, 0.75–0.82). The results demonstrated that HOXA13 is highly expressed in LUAD. In addition to the studies on HOXA13 expression in tissues, the expression data of HOXA13 in lung cancer cell lines were also collected from the CCLE database for further verification of these conclusions. Genes that were co-expressed with HOXA13 were identified for pathway analysis. The most enriched Gene Ontology terms in the genes co-expressed with HOXA13 were positive regulation of transcription from RNA polymerase II promoter, signal transduction and positive regulation of GTPase activity in biological process; cytoplasm, integral component of membrane and plasma membrane in cellular component; and significantly involved in protein binding, transcription factor activity, sequence-specific DNA binding and sequence-specific DNA binding in molecular function. Kyoto Encyclopedia of Genes and Genomes analysis revealed that these target genes were clearly involved in Pathways in cancer, Proteoglycans in cancer and cAMP signaling pathway. The hub genes obtained from the four protein-protein interaction networks were associated with HOXA13. The results of the bioinformatics research in the present study revealed that HOXA13 may influence the expression of these hub genes in such a way as to promote the occurrence and development of LUAD. In conclusion, the expression of HOXA13 in patients with LUAD and its potential clinical value were analyzed comprehensively in the present study using data from a variety of sources. Through bioinformatics analysis, evidence that HOXA13 may promote the occurrence and development of LUAD was obtained.

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“…The wound healing assay was carried out as previously described ( 28 ). Prior to co-culture, VSMCs were seeded on 6-well plates and scratched using a 200 µl pipette tip in order to generate a cell-free area.…”

Section: Methodsmentioning

confidence: 99%

DFMG reverses proliferation and migration of vascular smooth muscle cells induced by co-culture with injured vascular endothelial cells via suppression of the TLR4-mediated signaling pathway

Zhang

Huang

et al. 2018

Mol Med Report

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7-Difluoromethoxy-5,4′-dimethoxy-genistein (DFMG) is a novel chemical compound synthesized using genistein. Previous studies have indicated that DFMG can reverse the apoptosis of vascular endothelial cells (VECs) by regulating the mitochondrial apoptosis pathway. The present study aimed to investigate the activity and molecular mechanism underlying DFMG-mediated protection of vascular smooth muscle cell (VSMCs) using a non-contact co-culture model established by using Transwell insert. Secretion of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were measured by ELISA. Proliferation and migration of VSMCs were assessed using a Cell Counting kit-8 and wound healing assays, respectively. Toll-like receptor 4 (TLR4) mRNA and protein levels were detected by reverse transcription-quantitative polymerase chain reaction and western blotting analyses, respectively. In the present study, lysophosphatidylcholine (LPC) significantly increased the secretion of IL-6 and TNF-α in VECs. VECs treated with LPC markedly increased proliferation and migration of VSMCs, which were inhibited by DFMG. Transfection of either TLR4 short hairpin RNA (shRNA) or TLR4 cDNA in VECs inhibited and increased proliferation and migration of VSMCs, respectively. Furthermore, transfection of VECs with TLR4 shRNA suppressed the proliferation and migration of VSMCs induced by co-culture with injured VECs, which was further enhanced by treatment with DFMG. By contrast, transfection of VECs with TLR4 cDNA enhanced proliferation and migration of VSMCs and this effect was inhibited by treatment with DFMG. Taken together, the results of the present study demonstrated that DFMG can reverse proliferation and migration of VSMCs induced by co-culture with injured VECs via suppression of the TLR4-mediated signaling pathway.

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Smooth Muscle-Alpha Actin Inhibits Vascular Smooth Muscle Cell Proliferation and Migration by Inhibiting Rac1 Activity

Cited by 23 publications

References 31 publications

Vascular disease-causing mutation, smooth muscle α-actin R258C, dominantly suppresses functions of α-actin in human patient fibroblasts

Vascular disease-causing mutation, smooth muscle α-actin R258C, dominantly suppresses functions of α-actin in human patient fibroblasts

The expression of HOXA13 in lung adenocarcinoma and its clinical significance: A study based on The Cancer Genome Atlas, Oncomine and reverse transcription‑quantitative polymerase chain reaction

DFMG reverses proliferation and migration of vascular smooth muscle cells induced by co-culture with injured vascular endothelial cells via suppression of the TLR4-mediated signaling pathway

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