Hypoxia Affects Autophagy in Human Umbilical Vein Endothelial Cells via the IRE1 Unfolded Protein Response.

OBJECTIVE: The purpose of this study was to investigate the role of the unfolded protein response, specifically the inositol-requiring enzyme 1 (IRE1) signaling pathway, in hypoxia-induced autophagy in human umbilical venous endothelial cells (HUVECs). METHODS: The expression of IRE1 and autophagy relative protein in HUVECs with hypoxia was explored by Western blotting, qRT-PCR and confocal microscopy. Further, we evaluated the biological effects of HUVECs by tube formation assay and wound healing assay in vitro. Finally, we examined the function of IRE1 in local blood vessels through animal models. RESULTS: Hypoxia activated the IRE1 signaling pathway and induced autophagy in a time-dependent manner in HUVECs and further influenced the biological effects of HUVECs. Intraperitoneal injection of IRE1 inhibitors inhibited local vascular autophagy levels and lipid accumulation in model animals. CONCLUSION: Hypoxia can induce autophagy and activate the IRE1 signaling pathway in HUVECs and the IRE1 signaling pathway is involved in autophagy in hypoxic conditions.

Efficacy and safety analysis of new P2Y12 inhibitors versus clopidogrel in patients with percutaneous coronary intervention: a meta-analysis.

OBJECTIVE: New P2Y12 inhibitors, classified as oral (prasugrel and ticagrelor) and intravenous (cangrelor and elinogrel) drugs, have shown improved antithrombotic effects compared with clopidogrel in patients with acute coronary syndrome (ACS) or patients undergoing percutaneous coronary intervention (PCI) in landmark trials. The purpose of this study was to perform a meta-analysis of randomized trials that compared new P2Y12 inhibitors with clopidogrel to determine their efficacy and safety in patients undergoing PCI. METHODS: Randomized controlled trials of at least 4 weeks, comparing new P2Y12 inhibitors with clopidogrel in PCI, were identified using the electronic databases Cochrane Central Register of Controlled Trials, Medline, PubMed, Web of Science, and Google Scholar from January 1, 1980, to July 31, 2014. MAIN OUTCOME MEASURES: The primary efficacy endpoints were all-cause death and major adverse cardiovascular events (MACEs). The primary safety endpoint was thrombolysis in myocardial infarction (TIMI) major bleeding. RESULTS: Twelve studies including 71,097 patients met the inclusion criteria. New P2Y12 inhibitors significantly reduced all-cause death (odds ratio [OR]: 0.81; 95% confidence interval [CI] 0.73-0.90, p < 0.0001), MACEs (OR 0.81; 95% CI 0.73-0.90, p < 0.0001), stent thrombosis (OR 0.58; 95% CI 0.49-0.69, p < 0.00001), myocardial infarctions (OR 0.87; 95% CI 0.76-0.99, p = 0.03) and cardiovascular death (OR 0.82; 95% CI 0.73-0.92, p = 0.001) compared with clopidogrel. There were no significant differences between stroke (OR 0.87; 95% CI 0.72-1.05, p = 0.14) and major bleeding events (OR 1.22; 95% CI 0.99-1.52, p = 0.06) between the new P2Y12 inhibitor and clopidogrel groups. CONCLUSION: New P2Y12 inhibitors decreased death in patients undergoing PCI compared with clopidogrel with a considerable safety and tolerability profile; however, the risk/benefit ratio of ischemic and bleeding events should be further investigated.