Protective role of autophagy in AGE-induced early injury of human vascular endothelial cells

Xie, Yufeng; You, Shoujiang; Zhang, Yanlin; Han, Qiao; Cao, Yongjun; Xu, Xingshun; Yang, Yaping; Li, Jun; Liu, Chunfeng

doi:10.3892/mmr.2011.460

Cited by 47 publications

(43 citation statements)

References 27 publications

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“…Furthermore, AGEs enhanced BMDM cells polarization into M1 macrophage with producing IL-6 and TNF-a proinflammatory cytokines and upregulating the expressions of CD11c and CD86 through activating RAGE/NF-κB pathway in mice33. In addition, AGEs has been shown to induce autophagy in some cells, such as hepatic stellate cells34, cardimyocytes35, vascular smooth muscle cells36, and endothelial cells37. Our results for the first time show that AGEs could stimulate M1 polarized macrophage by inducing autophagy.…”

Section: Discussionmentioning

confidence: 58%

AGEs Induced Autophagy Impairs Cutaneous Wound Healing via Stimulating Macrophage Polarization to M1 in Diabetes

Guo

Cai

et al. 2016

Sci Rep

105

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Autophagy is essential in physiological and pathological processes, however, the role of autophagy in cutaneous wound healing and the underlying molecular mechanism remain elusive. We hypothesized that autophagy plays an important role in regulating wound healing. Here, we show that enhanced autophagy negatively impacts on normal cutaneous healing process and is related to chronic wounds as demonstrated by the increased LC3 in diabetic mice skin or patients’ chronic wounds. In addition, inhibition of autophagy by 3-MA restores delayed healing in C57BL/6 or db/db mice, demonstrating that autophagy is involved in regulating wound healing. Furthermore, we identify that macrophage is a major cell type underwent autophagy in wounds and increased autophagy induces macrophages polarization into M1 with elevated CD11c population and gene expressions of proinflammatory cytokines. To explore the mechanism underlying autophagy-impaired wound healing, we tested the role of IRF8, a regulator of autophagy, in autophagy-modulated macrophages polarization. IRF8 activation is up-regulating autophagy and M1 polarization of macrophages after AGEs (advanced glycation endproducts) treatment, blocking the IRF8 with shIRF8 inhibits autophagic activity and M1 polarization. In summary, this study elucidates that AGEs induces autophagy and modulates macrophage polarization to M1 via IRF8 activation in impairment of cutaneous wound healing.

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Section: Discussionmentioning

confidence: 58%

AGEs Induced Autophagy Impairs Cutaneous Wound Healing via Stimulating Macrophage Polarization to M1 in Diabetes

Guo

Cai

et al. 2016

Sci Rep

105

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“…For example, activation of autophagy maintains cell viability in endothelial cells exposed hemin 34 and advanced glycation end-products 35 . Furthermore, the polyphenolic compound curcumin increased endothelial cell survival following hydrogen peroxide exposure in a manner that depended on activation of autophagy via inhibition of mTOR and activation of FOXO1.…”

Section: Discussionmentioning

confidence: 99%

Restoration of autophagy in endothelial cells from patients with diabetes mellitus improves nitric oxide signaling

et al. 2016

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Background Endothelial dysfunction contributes to cardiovascular disease in diabetes mellitus. Autophagy is a multistep mechanism for removal of damaged proteins and organelles from the cell. Under diabetic conditions, inadequate autophagy promotes cellular dysfunction and insulin resistance in non-vascular tissue. We hypothesized that impaired autophagy contributes to endothelial dysfunction in diabetes mellitus. Methods and Results We measured autophagy markers and endothelial nitric oxide synthase (eNOS) activation in freshly isolated endothelial cells from diabetic subjects (n=45) and non-diabetic controls (n=41). p62 levels were higher in cells from diabetics (34.2±3.6 vs. 20.0±1.6, P=0.001), indicating reduced autophagic flux. Bafilomycin inhibited insulin-induced activation of eNOS (−21±5% vs. 64±22%, P=0.003) in cells from controls, confirming that intact autophagy is necessary for eNOS signaling. In endothelial cells from diabetics, activation of autophagy with spermidine restored eNOS activation, suggesting that impaired autophagy contributes to endothelial dysfunction (P=0.01). Indicators of autophagy initiation including the number of LC3-bound puncta and beclin 1 expression were similar in diabetics and controls, whereas an autophagy terminal phase indicator, the lysosomal protein Lamp2a, was higher in diabetics. In endothelial cells under diabetic conditions, the beneficial effect of spermidine on eNOS activation was blocked by autophagy inhibitors bafilomycin or 3-methyladenine. Blocking the terminal stage of autophagy with bafilomycin increased p62 (P=0.01) in cells from diabetics to a lesser extent than in cells from controls (P=0.04), suggesting ongoing, but inadequate autophagic clearance. Conclusion Inadequate autophagy contributes to endothelial dysfunction in patients with diabetes and may be a target for therapy of diabetic vascular disease.

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“…Some studies show that autophagy protects HUVECs from AGE-induced injury2526. However, the detailed protective mechanism of autophagy is still unclear.…”

Section: Discussionmentioning

confidence: 99%

“…The cytoplasmic form of LC3 (LC3-I) becomes membrane-associated (LC3-II) to form autophagosome during autophagy24. Many studies show a protective role of autophagy in AGE-induced injury in HUVECs2526. Considering the possibility of PLZF-mediated autophagy, FIR-induced PLZF nuclear translocation may protect vascular endothelial cells from AGE-induced injury.…”

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confidence: 99%

Far-infrared protects vascular endothelial cells from advanced glycation end products-induced injury via PLZF-mediated autophagy in diabetic mice

Chen

et al. 2017

Sci Rep

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The accumulation of advanced glycation end products (AGEs) in diabetic patients induces vascular endothelial injury. Promyelocytic leukemia zinc finger protein (PLZF) is a transcription factor that can be activated by low-temperature far-infrared (FIR) irradiation to exert beneficial effects on the vascular endothelium. In the present study, we investigated the influence of FIR-induced PLZF activation on AGE-induced endothelial injury both in vitro and in vivo. FIR irradiation inhibited AGE-induced apoptosis in human umbilical vein endothelial cells (HUVECs). PLZF activation increased the expression of phosphatidylinositol-3 kinases (PI3K), which are important kinases in the autophagic signaling pathway. FIR-induced PLZF activation led to autophagy in HUVEC, which was mediated through the upregulation of PI3K. Immunofluorescence staining showed that AGEs were engulfed by HUVECs and localized to lysosomes. FIR-induced autophagy promoted AGEs degradation in HUVECs. In nicotinamide/streptozotocin-induced diabetic mice, FIR therapy reduced serum AGEs and AGEs deposition at the vascular endothelium. FIR therapy also reduced diabetes-induced inflammatory markers in the vascular endothelium and improved vascular endothelial function. These protective effects of FIR therapy were not found in PLZF-knockout mice. Our data suggest that FIR-induced PLZF activation in vascular endothelial cells protects the vascular endothelium in diabetic mice from AGE-induced injury.

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Protective role of autophagy in AGE-induced early injury of human vascular endothelial cells

Cited by 47 publications

References 27 publications

AGEs Induced Autophagy Impairs Cutaneous Wound Healing via Stimulating Macrophage Polarization to M1 in Diabetes

AGEs Induced Autophagy Impairs Cutaneous Wound Healing via Stimulating Macrophage Polarization to M1 in Diabetes

Restoration of autophagy in endothelial cells from patients with diabetes mellitus improves nitric oxide signaling

Far-infrared protects vascular endothelial cells from advanced glycation end products-induced injury via PLZF-mediated autophagy in diabetic mice

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