Редактирование: SQSTM1

Sequestosome-1 (EBI3-associated protein of 60 kDa) (EBIAP) (p60) (Phosphotyrosine-independent ligand for the Lck SH2 domain of 62 kDa) (Ubiquitin-binding protein p62) [ORCA] [OSIL]

==Publications==

{{medline-entry
|title=The selective autophagy receptor [[SQSTM1]]/p62 improves lifespan and proteostasis in an evolutionarily conserved manner.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32041473
|abstract=The degradation of specific cargos such as ubiquitinated protein aggregates and dysfunctional mitochondria via macroautophagy/autophagy is facilitated by [[SQSTM1]]/p62, the first described selective autophagy receptor in metazoans. While the general process of autophagy plays crucial roles during aging, it remains unclear whether and how selective autophagy mediates effects on longevity and health. Two recent studies in the nematode [i]Caenorhabditis elegans[/i] and the fruit fly [i]Drosophila[/i] melanogaster observed gene expression changes of the respective [[SQSTM1]] orthologs in response to environmental stressors or age and showed that overexpression of [[SQSTM1]] is sufficient to extend lifespan and improve proteostasis and mitochondrial function in an autophagy-dependent manner in these model organisms. These findings show that increased expression of the selective autophagy receptor [[SQSTM1]] is sufficient to induce aggrephagy in [i]C. elegans[/i], and mitophagy in [i]Drosophila[/i], and demonstrate an evolutionarily conserved role for [[SQSTM1]] in lifespan determination.

|keywords=* Aging
* C. elegans
* Drosophila
* SQST-1
* SQSTM1
* aggrephagy
* heat shock
* mitophagy
* p62
* proteostasis
* ref(2)P
* selective autophagy
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138197
}}
{{medline-entry
|title=[[SQSTM1]]/p62 and [[PPARGC1A]]/PGC-1alpha at the interface of autophagy and vascular senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31441382
|abstract=Defective macroautophagy/autophagy and mitochondrial dysfunction are known to stimulate senescence. The mitochondrial regulator [[PPARGC1A]] (peroxisome proliferator activated receptor gamma, coactivator 1 alpha) regulates mitochondrial biogenesis, reducing senescence of vascular smooth muscle cells (VSMCs); however, it is unknown whether autophagy mediates [[PPARGC1A]]-protective effects on senescence. Using [i]ppargc1a [/i] VSMCs, we identified the autophagy receptor [[SQSTM1]]/p62 (sequestosome 1) as a major regulator of autophagy and senescence of VSMCs. Abnormal autophagosomes were observed in VSMCs in aortas of [i]ppargc1a [/i] mice. [i]ppargc1a [/i] VSMCs in culture presented reductions in LC3-II levels; in autophagosome number; and in the expression of [[SQSTM1]] (protein and mRNA), [[LAMP2]] (lysosomal-associated membrane protein 2), [[CTSD]] (cathepsin D), and [[TFRC]] (transferrin receptor). Reduced [[SQSTM1]] protein expression was also observed in aortas of [i]ppargc1a [/i] mice and was upregulated by [[PPARGC1A]] overexpression, suggesting that [[SQSTM1]] is a direct target of [[PPARGC1A]]. Inhibition of autophagy by 3-MA (3 methyladenine), spautin-1 or [i]Atg5[/i] (autophagy related 5) siRNA stimulated senescence. Rapamycin rescued the effect of [i]Atg5[/i] siRNA in [i]Ppargc1a [/i] , but not in [i]ppargc1a [/i] VSMCs, suggesting that other targets of [[MTOR]] (mechanistic target of rapamycin kinase), in addition to autophagy, also contribute to senescence. [i]Sqstm1[/i] siRNA increased senescence basally and in response to [[AGT]] II (angiotensin II) and zinc overload, two known inducers of senescence. Furthermore, [i]Sqstm1 [/i]gene deficiency mimicked the phenotype of [i]Ppargc1a[/i] depletion by presenting reduced autophagy and increased senescence [i]in vitro[/i] and [i]in vivo[/i]. Thus, [[PPARGC1A]] upregulates autophagy reducing senescence by a [[SQSTM1]]-dependent mechanism. We propose [[SQSTM1]] as a novel target in therapeutic interventions reducing senescence. 3-MA: 3 methyladenine; ACTA2/SM-actin: actin, alpha 2, smooth muscle, aorta; ACTB/β-actin: actin beta; [[AGT]] II: angiotensin II; ATG5: autophagy related 5; BECN1: beclin 1; CAT: catalase; CDKN1A: cyclin-dependent kinase inhibitor 1A (P21); Chl: chloroquine; [[CTSD]]: cathepsin D; CYCS: cytochrome C, somatic; DHE: dihydroethidium; DPBS: Dulbecco's phosphate-buffered saline; EL: elastic lamina; EM: extracellular matrix; FDG: fluorescein-di-β-D-galactopyranoside; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; γH2AFX: phosphorylated H2A histone family, member X, H DCFDA: 2',7'-dichlorodihydrofluorescein diacetate; [[LAMP2]]: lysosomal-associated membrane protein 2; MASMs: mouse vascular smooth muscle cells; MEF: mouse embryonic fibroblast; [[NBR1]]: [[NBR1]], autophagy cargo receptor; NFKB/NF-κB: nuclear factor of kappa light polypeptide gene enhancer in B cells; [[MTOR]]: mechanistic target of rapamycin kinase; NFE2L2: nuclear factor, erythroid derived 2, like 2; NOX1: NADPH oxidase 1; OPTN: optineurin; PFA: paraformaldehyde; PFU: plaque-forming units; [[PPARGC1A]]/PGC-1α: peroxisome proliferator activated receptor, gamma, coactivator 1 alpha; Ptdln3K: phosphatidylinositol 3-kinase; RASMs: rat vascular smooth muscle cells; ROS: reactive oxygen species; SA-GLB1/β-gal: senescence-associated galactosidase, beta 1; SASP: senescence-associated secretory phenotype; SIRT1: sirtuin 1; Spautin 1: specific and potent autophagy inhibitor 1; [[SQSTM1]]/p62: sequestosome 1; SOD: superoxide dismutase; TEM: transmission electron microscopy; TFEB: transcription factor EB; [[TFRC]]: transferrin receptor; TRP53/p53: transformation related protein 53; TUBG1: tubulin gamma 1; VSMCs: vascular smooth muscle cells; WT: wild type.

|keywords=* Aging
* SQSTM1
* autophagy
* oxidative stress
* senescence
* vascular biology
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469683
}}
{{medline-entry
|title=[[SIRT2]] functions in aging, autophagy, and apoptosis in post-maturation bovine oocytes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31295472
|abstract=Sirtuins have been implicated in the aging process, however, the functions of [[SIRT2]] in post-maturation aging of oocytes are not fully understood. The purpose of the present investigation was to assess the roles of [[SIRT2]] in aged oocytes and mechanisms involved. The fresh MII oocytes were aging in vitro, and treated with [[SIRT2]] inhibitor (SirReal2), autophagy activator (Rapamycin), and autophagy inhibitor (3-Ma) for 24 h, respectively. Oocyte activation, cytoplasmic fragmentation, and spindle defects, mitochondrial distribution, ROS levels, ATP production, mitochondrial membrane potential, and early apoptosis were investigated. Western blotting was performed to determine LC3-II accumulation, [[SQSTM1]] degradation, and caspase-3 activity. [[SIRT2]] expression gradually decreased in a time-dependent manner during oocyte aging. Treatment with SirReal2 significantly increased the rates of oocyte activation, cytoplasmic fragmentation, and spindle defects. In particular, the high ROS levels, abnormal mitochondrial distribution, low ATP production, and lost ΔΨm were observed in SirReal2-exposed oocytes. Further analysis revealed that LC3-II accumulation and [[SQSTM1]] degradation were induced by [[SIRT2]] inhibition. By performing early apoptosis analysis showed that oocyte aging was accompanied with cellular apoptosis, and [[SIRT2]] inhibition increased apoptosis rates of aged oocytes. Importantly, upregulating autophagy with Rapamycin could mimic the effects of [[SIRT2]] inhibition on apoptosis by increasing caspase-3 activation, whereas downregulating autophagy with 3-MA could abolish those effects by blocking caspase-3 activation. Our results suggest that [[SIRT2]] inactivation is a key mechanism underlying of cellular aging, and [[SIRT2]] inhibition contributes to autophagy-dependent cellular apoptosis in post-maturation oocytes.
|mesh-terms=* Acetamides
* Animals
* Apoptosis
* Autophagy
* Cattle
* Cellular Senescence
* Female
* Membrane Potential, Mitochondrial
* Mitochondria
* Oocytes
* Sirolimus
* Sirtuin 2
* Thiazoles
|keywords=* SIRT2
* aging
* apoptosis
* autophagy
* oocyte
|full-text-url=https://sci-hub.do/10.1016/j.lfs.2019.116639
}}
{{medline-entry
|title=A pH probe inhibits senescence in mesenchymal stem cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30526663
|abstract=Bone marrow-derived mesenchymal stem cells (BMSCs) are gradually getting attention because of its multi-directional differentiation potential, hematopoietic support, and promotion of stem cell implantation. However, cultured BMSCs in vitro possess a very limited proliferation potential, and the presence of stem cell aging has substantially restricted the effect together with the efficiency in clinical treatment. Recently, increasing attention has been paid to the connection between cellular aging and lysosomal acidification as new reports indicated that vacuolar H -ATPase (v-ATPase) activity was altered and lysosomal pH was dysregulated in the process of cellular aging. Therefore, promoting lysosomal acidification might contribute to inhibition of cell senescence. Our previous studies showed that a novel small molecule, 3-butyl-1-chloro imidazo [1, 5-a] pyridine-7-carboxylic acid (SGJ), could selectively and sensitively respond to acidic pH with fast response (within 3 min), but whether SGJ can promote lysosomal acidification and inhibit senescence in BMSCs is unknown. Rat BMSCs were cultured based on our system that had been already documented. BMSCs were treated with SGJ and/or Bafilomycin-A1 (Baf-A1). The co-localization between SGJ and lysosomes was assessed by a confocal microscope. Acridine orange (AO) staining and the Lysosensor™ Green DND-189 reagents were used for indicating changes in lysosomal concentration of H . Changes of senescence were detected by immunoblotting of p21 and senescence-associated beta-galactosidase (SA-β-gal) staining as well as immunofluorescence assay of senescence-associated heterochromatin foci (SAHF). Changes of autophagy were detected by immunoblotting of MAP1LC3 (LC3B) and [[SQSTM1]] (p62). Cell proliferation was determined by flow cytometry. Cell viability was calculated by sulforhodamine B assay (SRB). The V0 proton channel of v-ATPase was knocked down by transfecting with its small interfering RNA (si-[[ATP6V0C]]). Our work showed that SGJ can promote lysosomal acidification and inhibit senescence in BMSCs. Firstly, SGJ and lysosomes were well co-located in senescent BMSCs with the co-localization coefficient of 0.94. Secondly, SGJ increased the concentration of H  and the protein expression of lysosome-associated membrane protein 1 ([[LAMP1]]) and lysosome-associated membrane protein 2 ([[LAMP2]]). Thirdly, SGJ suppressed the expression of p21 in the senescent BMSCs and reduced SA-β-gal positive cells. Fourthly, SGJ promoted senescent BMSCs' proliferation and protein level of LC3B but reduced the p62/[[SQSTM1]] protein level. Furthermore, experimental group pretreated with 20 μM SGJ showed a stronger red fluorescent intensity, thinner cell morphology, less SA-β-gal positive cell, and less p21 protein level as well as higher cell viability in the presence of Baf-A1. Notably, [[ATP6V0C]] knockdown decreased the activity of v-ATPase and SGJ increased the concentration of H . Our work showed that SGJ could inhibit senescence in BMSCs and protect lysosomes by promoting expression of [[LAMP1]] and [[LAMP2]]. Meanwhile, SGJ could promote autophagy. Furthermore, our study also suggested that SGJ was a new Baf-A1 antagonist because SGJ could target and occupy the V0 proton channel of v-ATPase.
|mesh-terms=* Animals
* Biomarkers
* Cell Proliferation
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p21
* Hydrogen-Ion Concentration
* Lysosomal-Associated Membrane Protein 1
* Lysosomal-Associated Membrane Protein 2
* Lysosomes
* Macrolides
* Male
* Mesenchymal Stem Cells
* Models, Biological
* Molecular Probes
* Rats, Wistar
* Up-Regulation
* Vacuolar Proton-Translocating ATPases
* beta-Galactosidase
|keywords=* Autophagy
* Bafilomycin-A1 antagonist
* Bone marrow-derived mesenchymal stem cells
* Senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286523
}}
{{medline-entry
|title=The [[ATG5]]-binding and coiled coil domains of [[ATG16L1]] maintain autophagy and tissue homeostasis in mice independently of the WD domain required for LC3-associated phagocytosis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30403914
|abstract=Macroautophagy/autophagy delivers damaged proteins and organelles to lysosomes for degradation, and plays important roles in maintaining tissue homeostasis by reducing tissue damage. The translocation of LC3 to the limiting membrane of the phagophore, the precursor to the autophagosome, during autophagy provides a binding site for autophagy cargoes, and facilitates fusion with lysosomes. An autophagy-related pathway called LC3-associated phagocytosis (LAP) targets LC3 to phagosome and endosome membranes during uptake of bacterial and fungal pathogens, and targets LC3 to swollen endosomes containing particulate material or apoptotic cells. We have investigated the roles played by autophagy and LAP in vivo by exploiting the observation that the WD domain of [[ATG16L1]] is required for LAP, but not autophagy. Mice lacking the linker and WD domains, activate autophagy, but are deficient in LAP. The LAP  mice survive postnatal starvation, grow at the same rate as littermate controls, and are fertile. The liver, kidney, brain and muscle of these mice maintain levels of autophagy cargoes such as LC3 and [[SQSTM1]]/p62 similar to littermate controls, and prevent accumulation of [[SQSTM1]] inclusions and tissue damage associated with loss of autophagy. The results suggest that autophagy maintains tissue homeostasis in mice independently of LC3-associated phagocytosis. Further deletion of glutamate E230 in the coiled-coil domain required for [[WIPI2]] binding produced mice with defective autophagy that survived neonatal starvation. Analysis of brain lysates suggested that interactions between [[WIPI2]] and [[ATG16L1]] were less critical for autophagy in the brain, which may allow a low level of autophagy to overcome neonatal lethality. Abbreviations: CCD: coiled-coil domain; CYBB/NOX2: cytochrome b-245: beta polypeptide; GPT/ALT: glutamic pyruvic transaminase: soluble; LAP: LC3-associated phagocytosis; LC3: microtubule-associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; NOD: nucleotide-binding oligomerization domain; NADPH: nicotinamide adenine dinucleotide phosphate; RUBCN/Rubicon: RUN domain and cysteine-rich domain containing Beclin 1-interacting protein; SLE: systemic lupus erythematosus; [[SQSTM1]]/p62: sequestosome 1; TLR: toll-like receptor; TMEM: transmembrane protein; TRIM: tripartite motif-containing protein; UVRAG: UV radiation resistance associated gene; WD: tryptophan-aspartic acid; WIPI: WD 40 repeat domain: phosphoinositide interacting.
|mesh-terms=* Animals
* Autophagy
* Autophagy-Related Protein 5
* Autophagy-Related Proteins
* Brain
* Carrier Proteins
* Cytokines
* Female
* Fibroblasts
* Homeostasis
* Kidney
* Liver
* Longevity
* Macrophages
* Male
* Mice
* Mice, Inbred C57BL
* Mice, Transgenic
* Microtubule-Associated Proteins
* Muscles
* Phagocytosis
* Phagosomes
* WD40 Repeats
|keywords=* ATG16L1
* LC3-associated phagocytosis
* WD domain
* WIPI2
* brain
* sequestosome 1/p62 inclusions
* tissue homeostasis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526875
}}
{{medline-entry
|title=Systemic overexpression of [[SQSTM1]]/p62 accelerates disease onset in a [[SOD1]] -expressing ALS mouse model.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29843805
|abstract=Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by a selective loss of upper and lower motor neurons. Recent studies have shown that mutations in [[SQSTM1]] are linked to ALS. [[SQSTM1]] encodes [[SQSTM1]]/p62 that regulates not only autophagy via the association with MAP1LC3/LC3 and ubiquitinated proteins but also the [[KEAP1]]-NFE2L2/Nrf2 anti-oxidative stress pathway by interacting with [[KEAP1]]. Previously, we have demonstrated that loss of [[SQSTM1]] exacerbates disease phenotypes in a [[SOD1]] -expressing ALS mouse model. To clarify the effects of [[SQSTM1]] overexpression in this model, we generated [[SQSTM1]] and [[SOD1]]   double-transgenic ([[SQSTM1]];[[SOD1]]   ) mice. [[SQSTM1]];[[SOD1]]   mice exhibited earlier disease onset and shorter lifespan than did [[SOD1]]   mice. Conversely, disease progression after the onset rather slightly but significantly slowed in [[SQSTM1]];[[SOD1]]   mice. However, there were observable differences neither in the number of Nissl positive neurons nor in the distribution of ubiquitin-positive and/or [[SQSTM1]]-positive aggregates between [[SOD1]]   and [[SQSTM1]];[[SOD1]]   mice. It was noted that these protein aggregates were mainly observed in neuropil, and partly localized to astrocytes and/or microglia, but not to [[MAP2]]-positive neuronal cell bodies and dendrites at the end-stage of disease. Nonetheless, the biochemically-detectable insoluble [[SQSTM1]] and poly-ubiquitinated proteins were significantly and progressively increased in the spinal cord of [[SQSTM1]];[[SOD1]]   mice compared to [[SOD1]]   mice. These results suggest that overexpression of [[SQSTM1]] in [[SOD1]]   mice accelerates disease onset by compromising the protein degradation pathways.
|mesh-terms=* Amyotrophic Lateral Sclerosis
* Animals
* Anterior Horn Cells
* Body Weight
* Cell Count
* Disease Models, Animal
* Disease Progression
* Female
* Longevity
* Lumbar Vertebrae
* Mice, Inbred C57BL
* Mice, Transgenic
* Motor Neurons
* Neuroglia
* Phosphorylation
* Polyubiquitin
* Protein Aggregates
* Protein Folding
* Sequestosome-1 Protein
* Solubility
* Superoxide Dismutase-1
* Survival Analysis
* Tissue Distribution
* Ubiquitination
|keywords=* Amyotrophic lateral sclerosis
* SOD1
* SQSTM1/p62
* Ubiquitin-positive aggregates
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975400
}}
{{medline-entry
|title=[[SIRT6]] histone deacetylase functions as a potential oncogene in human melanoma.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29234488
|abstract=Melanoma is an aggressive skin cancer that can rapidly metastasize to become fatal, if not diagnosed early. Despite recent therapeutic advances, management of melanoma remains difficult. Therefore, novel molecular targets and strategies are required to manage this neoplasm. This study was undertaken to determine the role of the sirtuin [[SIRT6]] in melanoma. Employing a panel of human melanoma cells and normal human melanocytes, we found significant [[SIRT6]] mRNA and protein upregulation in melanoma cells. Further, using a tissue microarray coupled with quantitative Vectra analysis, we demonstrated significant [[SIRT6]] overexpression in human melanoma tissues. Lentiviral short hairpin RNA-mediated knockdown of [[SIRT6]] in A375 and Hs 294T human melanoma cells significantly decreased cell growth, viability, and colony formation, induced G1-phase arrest and increased senescence-associated beta-galactosidase staining. As autophagy is important in melanoma and is associated with [[SIRT6]], we used a qPCR array to study [[SIRT6]] knockdown in A375 cells. We found significant modulation in several genes and/or proteins (decreases in [[AKT1]], [[ATG12]], [[ATG3]], [[ATG7]], [[BAK1]], [[BCL2L1]], [[CLN3]], [[CTSB]], [[CTSS]], [[DRAM2]], [[HSP90AA1]], [[IRGM]], [[NPC1]], [[SQSTM1]], [[TNF]], and BECN1; increases in [[GAA]], ATG10). Our data suggests that increased [[SIRT6]] expression may contribute to melanoma development and/or progression, potentially via senescence-and autophagy-related pathways.

|keywords=* SIRT6
* autophagy
* melanoma
* senescence
* sirtuins
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5724804
}}
{{medline-entry
|title=[[SQSTM1]]/p62 mediates crosstalk between autophagy and the UPS in DNA repair.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27391408
|abstract=[[SQSTM1]]/p62 (sequestosome 1) selectively targets polyubiquitinated proteins for degradation via macroautophagy and the proteasome. Additionally, [[SQSTM1]] shuttles between the cytoplasmic and nuclear compartments, although its role in the nucleus is relatively unknown. Here, we report that [[SQSTM1]] dynamically associates with DNA damage foci (DDF) and regulates DNA repair. Upon induction of DNA damage [[SQSTM1]] interacts with [[FLNA]] (filamin A), which has previously been shown to recruit DNA repair protein [[RAD51]] ([[RAD51]] recombinase) to double-strand breaks and facilitate homologous recombination ([[HR]]). [[SQSTM1]] promotes proteasomal degradation of [[FLNA]] and [[RAD51]] within the nucleus, resulting in reduced levels of nuclear [[RAD51]] and slower DNA repair. [[SQSTM1]] regulates the ratio between [[HR]] and nonhomologous end joining (NHEJ) by promoting the latter at the expense of the former. This [[SQSTM1]]-dependent mechanism mediates the effect of macroautophagy on DNA repair. Moreover, nuclear localization of [[SQSTM1]] and its association with DDF increase with aging and are prevented by life-span-extending dietary restriction, suggesting that an imbalance in the mechanism identified here may contribute to aging and age-related diseases.
|mesh-terms=* Animals
* Autophagy
* Cell Nucleus
* DNA Damage
* DNA Repair
* Filamins
* Kinetics
* Mice, Inbred C57BL
* Models, Biological
* Proteasome Endopeptidase Complex
* Protein Transport
* Proteolysis
* Rad51 Recombinase
* Sequestosome-1 Protein
* Ubiquitin
|keywords=* DNA damage
* SQSTM1
* aging
* autophagy
* homologous recombination
* nonhomologous end joining
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391493
}}
{{medline-entry
|title=Defective autophagy in vascular smooth muscle cells accelerates senescence and promotes neointima formation and atherogenesis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26391655
|abstract=Autophagy is triggered in vascular smooth muscle cells (VSMCs) of diseased arterial vessels. However, the role of VSMC autophagy in cardiovascular disease is poorly understood. Therefore, we investigated the effect of defective autophagy on VSMC survival and phenotype and its significance in the development of postinjury neointima formation and atherosclerosis. Tissue-specific deletion of the essential autophagy gene Atg7 in murine VSMCs (atg7  VSMCs) caused accumulation of [[SQSTM1]]/p62 and accelerated the development of stress-induced premature senescence as shown by cellular and nuclear hypertrophy, [[[[CDKN2A]]]]-RB-mediated G  proliferative arrest and senescence-associated [[GLB1]] activity. Transfection of [[SQSTM1]]-encoding plasmid DNA in Atg7  VSMCs induced similar features, suggesting that accumulation of [[SQSTM1]] promotes VSMC senescence. Interestingly, atg7  VSMCs were resistant to oxidative stress-induced cell death as compared to controls. This effect was attributed to nuclear translocation of the transcription factor [[NFE2L2]] resulting in upregulation of several antioxidative enzymes. In vivo, defective VSMC autophagy led to upregulation of [[MMP9]], TGFB and [[CXCL12]] and promoted postinjury neointima formation and diet-induced atherogenesis. Lesions of VSMC-specific atg7 knockout mice were characterized by increased total collagen deposition, nuclear hypertrophy, [[[[CDKN2A]]]] upregulation, RB hypophosphorylation, and [[GLB1]] activity, all features typical of cellular senescence. To conclude, autophagy is crucial for VSMC function, phenotype, and survival. Defective autophagy in VSMCs accelerates senescence and promotes ligation-induced neointima formation and diet-induced atherogenesis, implying that autophagy inhibition as therapeutic strategy in the treatment of neointimal stenosis and atherosclerosis would be unfavorable. Conversely, stimulation of autophagy could be a valuable new strategy in the treatment of arterial disease.

|keywords=* atherosclerosis
* autophagy
* neointima formation
* senescence
* sequestosome 1/p62
* vascular smooth muscle cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4824610
}}