Hydrogen sulfide decreases high glucose/palmitate-induced autophagy in endothelial cells by the Nrf2-ROS-AMPK signaling pathway

Abstract

BackgroundExcessive autophagy induced by extravagant oxidative stress is the main reason for diabetes-induced vascular endothelial cells dysfunction. Hydrogen sulfide (H2S) has anti-oxidative effects but its regulation on excessive autophagy of vascular endothelial cells is unclear.MethodsIn this study, aorta of db/db mice (28 weeks old) and rat aortic endothelial cells (RAECs) treated with 40 mM glucose and 500 μM palmitate acted as type II diabetic animal and cellular models, respectively, and 100 μMNaHS was used as an exogenous H2S donor. The apoptosis level was measured by terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL) staining and Hoechst 33342/PI staining. The activities of SOD, CAT and respiratory complexes were also measured. The mRNA levels of SOD and CAT were detected by real-time PCR. AMPK-siRNA was used to detect the effect of AMPK on autophagy. Western blotting was used to detected the protein level.ResultsH2S production was decreased (p < 0.05, p < 0.01) both in vitro and in vivo; NaHS treatment rescued this impairment (p < 0.05, p < 0.01). The expression of adhesive proteins was increased (p < 0.05, p < 0.01) both in vitro and in vivo; NaHS attenuated (p < 0.05, p < 0.01) these alterations. NaHS could protect endothelial cells against apoptosis induced by type II diabetes (p < 0.05, p < 0.01). Furthermore, the expressions and activities of SOD and CAT were impaired (p < 0.05, p < 0.01) in endothelial cells of diabetes II; NaHS treatment attenuated (p < 0.05) this impairment. NaHS also increased ATP production (p < 0.05) and activities of respiratory complexes (p < 0.05), and the ratio of p-AMPK to AMPK was also decreased by NaHS (p < 0.01). The level of autophagy in endothelial cells was also decreased (p < 0.05, p < 0.01) by NaHS treatment and AMPK-siRNA treatment. The expression of Nrf2 in the nuclei was increased (p < 0.05) by NaHS treatment.ConclusionExogenous H2S might protect arterial endothelial cells by suppressing excessive autophagy induced by oxidative stress through the Nrf2-ROS-AMPK signaling pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/s13578-016-0099-1) contains supplementary material, which is available to authorized users.

Cystathionine β‐synthase regulates mitochondrial morphogenesis in ovarian cancer

“…For instance, embryonic stem cells present a fragmented mitochondrial morphology for their survival (40). Interestingly, several papers have shown that CBS or H 2 S is required for induction of autophagy, and thus, the targeting of CBS or elimination of H 2 S abrogates autophagy (41,42). In the absence of autophagy or damaged mitochondria, MFNs can be additionally targeted by E3 ubiquitin ligases, such as March V (43), HUWE1 (38), and Mdm30 (44).…”

Exogenous H2S Protects Against Diabetic Cardiomyopathy by Activating Autophagy via the AMPK/mTOR Pathway

“…Activation of AMPK inhibits diabetes-induced cardiomyocyte apoptosis and prevents cardiac dysfunction in diabetic animals after treatment with metformin [9], suggesting that further investigations are needed to explain the role of AMPK in the regulation of autophagy and apoptosis. Interestingly, our previous study demonstrated that H 2 S inhibits induction of protein synthesis in the endothelial cells after high glucose treatment by activation of AMPK [56]. Indeed, activation of AMPK inhibits mTOR, the negative regulator of autophagy, and subsequently stimulates autophagy.…”

Functional and Molecular Insights of Hydrogen Sulfide Signaling and Protein Sulfhydration

“…Exogenous H2S protect arterial endothelial cells by suppressing excessive autophagy induced by oxidative stress through the Nrf2-ROSAMPK signaling pathway [53]. Myocardial fibrosis is the predominant pathological characteristic of diabetic myocardial damage.…”