Caveolin-1 Is a Critical Determinant of Autophagy, Metabolic Switching, and Oxidative Stress in Vascular Endothelium

Shiroto, Takashi; Romero, Natália; Sugiyama, Toru; Sartoretto, Juliano L.; Kalwa, Hermann; Yan, Zhonghua; Shimokawa, Hiroaki; Michel, Thomas

doi:10.1371/journal.pone.0087871

Cited by 109 publications

(82 citation statements)

References 46 publications

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“…19 Second, loss of CAV1 promotes autophagy via enhanced oxidative stress and NFKB1/NF-κB activation. 20,42 Third, a recent study provides direct evidence to show a competitive interaction of CAV1 and the ATG12-ATG5 system, which suppresses the formation and function of the ATG12-ATG5 complex in lung epithelial cells. 43 In contrast, some components of lipid rafts are reported to promote autophagy.…”

Section: Discussionmentioning

confidence: 99%

Critical role of CAV1/caveolin-1 in cell stress responses in human breast cancer cells via modulation of lysosomal function and autophagy

et al. 2015

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CAV1 (caveolin 1, caveolae protein, 22kDa) is well known as a principal scaffolding protein of caveolae, a specialized plasma membrane structure. Relatively, the caveolae-independent function of CAV1 is less studied. Autophagy is a process known to involve various membrane structures, including autophagosomes, lysosomes, and autolysosomes for degradation of intracellular proteins and organelles. Currently, the function of CAV1 in autophagy remains largely elusive. In this study, we demonstrate for the first time that CAV1 deficiency promotes both basal and inducible autophagy. Interestingly, the promoting effect was found mainly in the late stage of autophagy via enhancing lysosomal function and autophagosome-lysosome fusion. Notably, the regulatory function of CAV1 in lysosome and autophagy was found to be caveolae-independent, and acts through lipid rafts. Furthermore, the elevated autophagy level induced by CAV1 deficiency serves as a cell survival mechanism under starvation. Importantly, downregulation of CAV1 and enhanced autophagy level were observed in human breast cancer cells and tissues. Taken together, our data reveal a novel function of CAV1 and lipid rafts in breast cancer development via modulation of lysosomal function and autophagy.

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Section: Discussionmentioning

confidence: 99%

Critical role of CAV1/caveolin-1 in cell stress responses in human breast cancer cells via modulation of lysosomal function and autophagy

et al. 2015

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“…Zhang et al showed that glucose-induced ROS generation was significantly attenuated by the chemical disruption of caveolae in knockout mesangial cells [30] . Shiroto et al showed that mitochondrial ROS production was increased in endothelial cells after cav-1 knockdown, and their results established that cav-1 plays a key role in regulating oxidative stress in the endothelium and may represent a critical target in cardiovascular diseases [40] . Chanvorachote and Chunhacha showed that cav-1 regulates the endothelial adhesion of lung cancer cells via a ROS-dependent mechanism [41] .…”

Section: Discussionmentioning

confidence: 99%

Curcumin attenuates high glucose-induced podocyte apoptosis by regulating functional connections between caveolin-1 phosphorylation and ROS

et al. 2016

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Aim: Caveolin-1 (cav-1) is a major multifunctional scaffolding protein of caveolae. Cav-1 is primarily expressed in mesangial cells, renal proximal tubule cells and podocytes in kidneys. Recent evidence shows that the functional connections between cav-1 and ROS play a key role in many diseases. In this study we investigated whether regulating the functional connections between cav-1 and ROS in kidneys contributed to the beneficial effects of curcumin in treating diabetic nephropathy in vitro and in vivo. Methods: Cultured mouse podocytes (mpc5) were incubated in a high glucose (HG, 30 mmol/L) medium for 24, 48 or 72 h. Male rats were injected with STZ (60 mg/kg, ip) to induce diabetes. ROS generation, SOD activity, MDA content and caspase-3 activity in the cultured cells and kidney cortex homogenate were determined. Apoptotic proteins and cav-1 phosphorylation were analyzed using Western blot analyses. Results: Incubation in HG-containing medium time-dependently increased ROS production, oxidative stress, apoptosis, and cav-1 phosphorylation in podocytes. Pretreatment with curcumin (1, 5, and 10 μmol/L) dose-dependently attenuated these abnormalities in HG-treated podocytes. Furthermore, in HG-containing medium, the podocytes transfected with a recombinant plasmid GFP-cav-1 Y14F (mutation at a cav-1 phosphorylation site) exhibited significantly decreased ROS production and apoptosis compared with the cells transfected with empty vector. In diabetic rats, administration of curcumin (100 or 200 mg/kg body weight per day, ig, for 8 weeks) not only significantly improved the renal function, but also suppressed ROS levels, oxidative stress, apoptosis and cav-1 phosphorylation in the kidneys. Conclusion: Curcumin attenuates high glucose-induced podocyte apoptosis in vitro and diabetic nephropathy in vivo partly through regulating the functional connections between cav-1 phosphorylation and ROS.

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“…Fibroblasts and breast cancer cells in culture lacking caveolin-1 increase autophagy markers and LysoTracker-positive compartments in a response to increased oxidative stress (51,52). Notably, non-canonical autophagy shares components with clearance phagocytosis pathways (53,54).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Phagolysosomal Digestion by Caveolin-1 of the Retinal Pigment Epithelium Is Essential for Vision

Sethna

Chamakkala

et al. 2016

Journal of Biological Chemistry

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Caveolin-1 associates with the endo/lysosomal machinery of cells in culture, suggesting that it functions at these organelles independently of its contribution to cell surface caveolae. Here we explored mice lacking caveolin-1 specifically in the retinal pigment epithelium (RPE Support of the neural retina generally and of adjacent photoreceptor neurons specifically by the retinal pigment epithelium (RPE) 5 is essential for vision (1). A major function of the RPE is its contribution to photoreceptor outer segment renewal, a continuous and life-long rejuvenation process that involves the formation of new membrane disks at the proximal end of the outer segment and diurnal shedding of distal spent outer segment tips (2). Outer segment renewal is critical for photoreceptor function and survival, and any abnormality is thought to impair vision. RPE cells participate in outer segment renewal by clearing shed photoreceptor outer segment fragments (POS) by receptor-mediated phagocytosis (3).Mechanistically, RPE phagocytosis belongs to a family of conserved non-inflammatory clearance phagocytosis pathways that other cell types use to remove apoptotic cells and debris. These pathways have in common that their failure to efficiently clear debris contributes to human disease. However, unlike other forms of phagocytosis, RPE clearance of POS occurs in a strict diurnal rhythm that is regulated by light and circadian mechanisms (4). This is a unique advantage for RPE phagocytosis studies because all steps of the synchronized phagocytic process may be quantified precisely in situ in the intact, undisturbed retinas of experimental animals. Content in the RPE of engulfed rod POS phagosomes peaks shortly after light onset and declines characteristically within several hours as RPE cells complete digestion of their phagocytic load before the next burst of intake (5).Like other phagocytic pathways, ingested phagosomes in the RPE fuse with lysosomal vesicles to form phagolysosomes. In POS phagolysosomes, degradation of opsin, which constitutes ϳ85% of POS protein, requires the aspartic protease cathepsin D and phagosomal acidification (6, 7). Because RPE cells are post-mitotic in the mammalian eye and ingest numerous POS daily, prompt and complete POS engulfment is essential to prevent gradual buildup of undigested debris in the RPE (8). Inefficient RPE lysosomal function causes accumulation of debris in human and experimental animal RPE that can be toxic and

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Caveolin-1 Is a Critical Determinant of Autophagy, Metabolic Switching, and Oxidative Stress in Vascular Endothelium

Cited by 109 publications

References 46 publications

Critical role of CAV1/caveolin-1 in cell stress responses in human breast cancer cells via modulation of lysosomal function and autophagy

Critical role of CAV1/caveolin-1 in cell stress responses in human breast cancer cells via modulation of lysosomal function and autophagy

Curcumin attenuates high glucose-induced podocyte apoptosis by regulating functional connections between caveolin-1 phosphorylation and ROS

Regulation of Phagolysosomal Digestion by Caveolin-1 of the Retinal Pigment Epithelium Is Essential for Vision

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