Angiogenic factor AGGF1 blocks neointimal formation after vascular injury via interaction with integrin α7 on vascular smooth muscle cells

Yu, Yubing; Li, Yong; Peng, Huixin; Song, Qingwei; Da, Xing-Wen; Li, Hui; He, Zuhan; Ren, Xiang; Xu, Chengqi; Yao, Yufeng; Wang, Qing Kenneth

doi:10.1016/j.jbc.2022.101759

Cited by 12 publications

(14 citation statements)

References 30 publications

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“…The angiogenic factor AGGF1 is required for phenotypic transition, proliferation, migration, and cell cycle regulation of VSMCs, and recent studies have shown that AGGF1 co-acts with integrin α7, a receptor on VSMCs, to reduce the expression of synthetic markers in VSMCs and block neointima formation after vascular injury [ 60 ] ( Table 2 ).…”

Section: Cardiovascular Diseases Associated With Vsmcs Phenotypic Swi...mentioning

confidence: 99%

Vascular Smooth Muscle Cells Phenotypic Switching in Cardiovascular Diseases

Tang

Chen

Zhang

et al. 2022

Cells

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Vascular smooth muscle cells (VSMCs), the major cell type in the arterial vessel wall, have a contractile phenotype that maintains the normal vessel structure and function under physiological conditions. In response to stress or vascular injury, contractile VSMCs can switch to a less differentiated state (synthetic phenotype) to acquire the proliferative, migratory, and synthetic capabilities for tissue reparation. Imbalances in VSMCs phenotypic switching can result in a variety of cardiovascular diseases, including atherosclerosis, in-stent restenosis, aortic aneurysms, and vascular calcification. It is very important to identify the molecular mechanisms regulating VSMCs phenotypic switching to prevent and treat cardiovascular diseases with high morbidity and mortality. However, the key molecular mechanisms and signaling pathways participating in VSMCs phenotypic switching have still not been fully elucidated despite long-term efforts by cardiovascular researchers. In this review, we provide an updated summary of the recent studies and systematic knowledge of VSMCs phenotypic switching in atherosclerosis, in-stent restenosis, aortic aneurysms, and vascular calcification, which may help guide future research and provide novel insights into the prevention and treatment of related diseases.

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Section: Cardiovascular Diseases Associated With Vsmcs Phenotypic Swi...mentioning

confidence: 99%

Vascular Smooth Muscle Cells Phenotypic Switching in Cardiovascular Diseases

Tang

Chen

Zhang

et al. 2022

Cells

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“…Co‐immunoprecipitation was performed as described previously 34 . Protein extracts from HeLa cells were prepared by lysis buffer (Cat# P0013, Beyotime Biotechnology, Haimen, China) and a cocktail of protease inhibitors (Cat# 04693132001, Roche, Basel, Switzerland).…”

Section: Methodsmentioning

confidence: 99%

“…Co-immunoprecipitation was performed as described previously. 34 Protein extracts from HeLa cells were prepared by lysis buffer (Cat# P0013, Beyotime Biotechnology, Haimen, China) and a cocktail of protease inhibitors (Cat# 04693132001, Roche, Basel, Switzerland). After centrifugation, the supernatant (400 μg) was incubated with Mouse monoclonal anti-FLAG antibody (MBL International, Cat# M185-3S; RRID:AB_10971972), Mouse monoclonal anti-HA (MBL International, Cat# M180-3; RRID:AB_10951811), Mouse monoclonal anti-GFP (MBL International, Cat# M048-3; RRID:AB_591823), or Normal mouse IgG control (Santa cruz, Cat# sc-2025; RRID:AB_737182).…”

Section: Co-immunoprecipitation Analysis and Western Blot Analysismentioning

confidence: 99%

Identification and characterization of a special type of subnuclear structure: AGGF1‐coated paraspeckles

et al. 2022

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AGGF1 is an angiogenic factor with G‐Patch and FHA domains 1 described by our group. Gain‐of‐function mutations in AGGF1 cause Klippel–Trenaunay syndrome, whereas somatic loss‐of‐function mutations cause cancer. Paraspeckles are small membraneless subnuclear structures with a diameter of 0.5–1 μm, and composed of lncRNA NEAT1 as the scaffold and three core RNA‐binding proteins NONO, PSPC1, and PSF. Here, we show that AGGF1 is a key regulatory and structural component of paraspeckles that induces paraspeckle formation, forms an outside rim of paraspeckles, wraps around the NONO/PSF/PSPC1/NEAT1 core, and regulates the size and number of paraspeckles. AGGF1‐paraspeckles are larger (>1 μm) than conventional paraspeckles. RNA‐FISH in combination with immunostaining shows that AGGF1, NONO, and NEAT1_2 co‐localize in 20.58% of NEAT1_2‐positive paraspeckles. Mechanistically, AGGF1 interacts with NONO, PSF, and HNRNPK, and upregulates NEAT1_2, a longer, 23 kb NEAT1 transcript with a key role in regulation of paraspeckle size and number. RNA‐immunoprecipitation shows that AGGF1 interacts with NEAT1, which may be another possible mechanism underlying the formation of AGGF1‐paraspeckles. NEAT1_2 knockdown reduces the number and size of AGGF1‐paraspeckles. Functionally, AGGF1 regulates alternative RNA splicing as it decreases the exon skipping/inclusion ratio in a CD44 model. AGGF1 is also localized in some nuclear foci without NEAT1 or NONO, suggesting that AGGF1 is an important liquid–liquid phase separation (LLPS) driver for other types of AGGF1‐positive nuclear condensates (referred to as AGGF1‐bodies). Our results identify a special type of AGGF1‐coated paraspeckles and provide important insights into the formation, structure, and function of paraspeckles.

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“…All these data suggest that AGGF1 protein therapy can successfully attenuate pressure-overload-induced carotid artery dilatation, remodeling and inflammation, and VSMC proliferation by inhibiting TGF-β1 signaling and ERK1/2 signaling. We recently identified the AGGF1 receptor on VSMCs as integrin α7, and the AGGF1-receptor interaction involved the RDD motif at amino acid positions 606-608 in the AGGF1 protein and between the FHA domain and the G-patch domain 26 . The function of AGGF1 was impaired if the RDD residues were deleted (referred to as AGGF1-RDD del ) 26 .…”

Section: Recombinant Aggf1 Protein Attenuates Vascular Inflammation A...mentioning

confidence: 99%

“…AGGF1 is a master regulator for cell proliferation, migration, and differentiation, and acts at the top of the genetic regulatory system that promotes the differentiation of mesodermal cells into pluripotent hemangioblasts in zebrafish 23,24 . Recently, we identified the receptor for AGGF1 as integrin α5 on endothelial cells (ECs) 25 , and α7 on vascular smooth muscle cells (VSMCs) 26 . AGGF1 is also a key regulator for autophagy, ER stress, p53 stability, and alternative splicing 22,27 .…”

mentioning

confidence: 99%

AGGF1 therapy inhibits thoracic aortic aneurysms by enhancing integrin α7-mediated inhibition of TGF-β1 maturation and ERK1/2 signaling

Huang

et al. 2023

Nat Commun

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Thoracic aortic aneurysm (TAA) is a localized or diffuse dilatation of the thoracic aortas, and causes many sudden deaths each year worldwide. However, there is no effective pharmacologic therapy. Here, we show that AGGF1 effectively blocks TAA-associated arterial inflammation and remodeling in three different mouse models (mice with transverse aortic constriction, Fbn1C1041G/+ mice, and β-aminopropionitrile-treated mice). AGGF1 expression is reduced in the ascending aortas from the three models and human TAA patients. Aggf1+/- mice and vascular smooth muscle cell (VSMC)-specific Aggf1smcKO knockout mice show aggravated TAA phenotypes. Mechanistically, AGGF1 enhances the interaction between its receptor integrin α7 and latency-associated peptide (LAP)-TGF-β1, blocks the cleavage of LAP-TGF-β1 to form mature TGF-β1, and inhibits Smad2/3 and ERK1/2 phosphorylation in VSMCs. Pirfenidone, a treatment agent for idiopathic pulmonary fibrosis, inhibits TAA-associated vascular inflammation and remodeling in wild type mice, but not in Aggf1+/- mice. In conclusion, we identify an innovative AGGF1 protein therapeutic strategy to block TAA-associated vascular inflammation and remodeling, and show that efficacy of TGF-β inhibition therapies require AGGF1.

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Angiogenic factor AGGF1 blocks neointimal formation after vascular injury via interaction with integrin α7 on vascular smooth muscle cells

Cited by 12 publications

References 30 publications

Vascular Smooth Muscle Cells Phenotypic Switching in Cardiovascular Diseases

Vascular Smooth Muscle Cells Phenotypic Switching in Cardiovascular Diseases

Identification and characterization of a special type of subnuclear structure: AGGF1‐coated paraspeckles

AGGF1 therapy inhibits thoracic aortic aneurysms by enhancing integrin α7-mediated inhibition of TGF-β1 maturation and ERK1/2 signaling

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