Diabetic vascular complication accounts for disabilities and high mortality rates in diabetic patients. The accumulation of advanced glycation end products (AGE) in diabetic patients can trigger apoptotic changes of vascular endothelial cells and involves in the development and progression of micro- and macroangiopathy. Promyelocytic leukaemia zinc finger protein (PLZF) is a nuclear transcription factor and linked to tumor suppression. Recently, we found low-temperature FIR irradiation induced the nuclear translocation of PLZF in human umbilical vein endothelial cells (HUVECs), which upregulated PI3Ks to activate Akt and eNOS. PI3K/Akt signaling is a powerful pro-survival pathway. NO bioavailability is crucial for maintaining vascular endothelial health and function. Additionally, the PI3Ks (classes I and III) are also involved in autophagic signaling. Autophagy is potential to express a protective effect against apoptosis. Therefore, we hypothesize that PLZF nuclear translocation protects vascular endothelium cells from AGE-induced injury in vivo and in vitro. In this project, we will evaluate the influence of PLZF nuclear translocation on AGE-induced apoptosis and inflammatory responses in HUVECs. AGE-induced apoptosis is analyzed by annexin V staining and flow cytometry. Inflammatory mediators in HUVECs are monitored by ELISA kits and Western blot analysis. Treated cells are exposed to low-temperature FIR to induce PLZF nuclear translocation. PLZF-induced autophagy is identified by Cyto-ID Green autophagy detection. The data of cellular experiments will be further proved in streptozotocin(STZ)-induced diabetic mice. The damage of vascular endothelium in mice is evaluated by aorta ring assays and peripheral vessel immunohistochemistry. The PLZF knock-out mice are employed in this study to confirm the role of PLZF in the vascular protective effect. The specific aims of this project are listed as below: 1. Evaluate the influence of PLZF nuclear translocation on the AGE-induced apoptosis and inflammatory responses in HUVECs, and study its molecular mechanism. 2. Study the connection between PLZF nuclear translocation and autophagy in HUVECs. 3. Study the connection between PLZF-induced autophagy and the antiapoptotic effect in HUVECs. 4. Investigate the influence of PLZF nuclear translocation on the RAGE-mediated signaling pathway in HUVECs. 5. Evaluate protective effect of PLZF nuclear translocation on vascular endothelium in diabetic mice. By FIR irradiation, we can prove the protective effect of PLZF on vascular endothelium in diabetic vascular complications, and identify the detailed mechanism in this project. The finding in this project will provide a potential non-invasion therapy for diabetic vascular complications.
|Effective start/end date||8/1/15 → 7/31/16|
- Advanced glycation end products (AGEs)
- Promyelocytic leukaemia zinc finger protein (PLZF)