PMID- 33485865 OWN - NLM STAT- MEDLINE DCOM- 20210405 LR - 20210405 IS - 1532-8600 (Electronic) IS - 0026-0495 (Linking) VI - 117 DP - 2021 Apr TI - AGEs exacerbates coronary microvascular dysfunction in NoCAD by activating endoplasmic reticulum stress-mediated PERK signaling pathway. PG - 154710 LID - S0026-0495(21)00010-X [pii] LID - 10.1016/j.metabol.2021.154710 [doi] AB - OBJECTIVE: The current study was aimed to investigate the involvement of endoplasmic reticulum stress (ERS)-mediated protein kinase R-like endoplasmic reticulum kinase (PERK) signaling in advanced glycation end products (AGEs)-exacerbated coronary microvascular dysfunctions (CMD) in non-obstructive coronary artery disease (NoCAD). METHODS AND MATERIALS: ob/ob(-/-) mice were used as NoCAD animal model which were exposed to AGEs by intraperitoneal injections. Animal CMD was evaluated by coronary flow velocity reserve (CFVR). A viral vector carrying perk-siRNA was used to silence PERK in vivo and in vitro studies. Cell apoptosis was detected by TUNEL. Immunofluorescent staining was used to assess CD42c-positive cell number in cardiac sections and NFATc4 translocation in CMECs. Real-time PCR and Western blotting were used to evaluate the gene expression levels. Cytokine and AGEs concentrations were determined by ELISA. Enzymatic activity of CaN was measured by a colorimetric method. A registered cross sectional study consisted of 77 patients diagnosed as NoCAD was used to analyze the association between diabetes and CMD which was measured by index of microvascular resistance (IMR) with a pressure wire system. RESULTS: Significant CMD was found in NoCAD mice compared with healthy control. AGEs exposure exacerbated CMD in NoCAD animals which was improved by PERK silencing. Phosphorylation of PERK, nuclear translocation of nuclear factor of activated T-cells (NFAT)c4, enzymatic activity of calcineurin (CaN), expression levels of Fas/FasL, production of interleukin (IL)6, tumor necrosis factor (TNF)alpha, cyclooxygenase (COX)2, thromboxane B (TXB)2 as well as apoptosis were suppressed by PERK silencing in cardiac microcirculation endothelial cells (CMECs) isolated from AGEs-exposed NoCAD mice and AGEs-treated primary CMECs. PERK silencing also reduced CD42c-postive cells number in cardiac tissue from AGEs-exposed NoCAD mice. CONCLUSION: Diabetes was associated with CMD in NoCAD. AGEs fostered in diabetes exacerbated CMD by activating ERS-mediated PERK/CaN/NFATc4 signaling in CMECs. IMR values increased significantly in NoCAD patients complicated with diabetes, which were significantly and positively correlated with serum AGEs concentrations. CI - Copyright (c) 2021 Elsevier Inc. All rights reserved. FAU - Liu, Zhongwei AU - Liu Z AD - Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, Shaanxi Province 710072, China. FAU - Zhu, Haitao AU - Zhu H AD - Department of Pediatrics, Northwest Women's and Children's Hospital, Xi'an, Shaanxi Province 710000, China. FAU - Ma, Yanpeng AU - Ma Y AD - Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, Shaanxi Province 710072, China. FAU - Tang, Zhiguo AU - Tang Z AD - Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, Shaanxi Province 710072, China. FAU - Zhao, Na AU - Zhao N AD - Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, Shaanxi Province 710072, China. FAU - Wang, Yuan AU - Wang Y AD - Department of Preventive Medicine, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, Shaanxi Province 710072, China. Electronic address: ooozkb@sina.com. FAU - Pan, Shuo AU - Pan S AD - Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, Shaanxi Province 710072, China. Electronic address: parker1985@sina.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210122 PL - United States TA - Metabolism JT - Metabolism: clinical and experimental JID - 0375267 RN - 0 (Glycation End Products, Advanced) RN - EC 2.7.11.1 (EIF2AK3 protein, human) RN - EC 2.7.11.1 (eIF-2 Kinase) SB - IM MH - Animals MH - Apoptosis/physiology MH - Cell Line MH - Coronary Artery Disease/*metabolism/pathology MH - Coronary Vessels/metabolism/pathology MH - Cross-Sectional Studies MH - Diabetes Mellitus/metabolism/pathology MH - Diabetes Mellitus, Experimental/metabolism/pathology MH - Endoplasmic Reticulum/*metabolism/physiology MH - Endoplasmic Reticulum Stress/*physiology MH - Endothelial Cells/metabolism/pathology MH - Glycation End Products, Advanced/*metabolism MH - Humans MH - Mice MH - Mice, Inbred C57BL MH - Microcirculation/*physiology MH - Phosphorylation/physiology MH - Signal Transduction/*physiology MH - eIF-2 Kinase/*metabolism OTO - NOTNLM OT - Advanced glycation end products (AGEs) OT - Cardiac microvascular endothelial cells (CMECs) OT - Diabetes OT - Endoplasmic reticulum stress (ERS) OT - Microvascular dysfunction OT - Non-obstractive coronary artery disease (NoCAD) COIS- Declaration of competing interest The authors declare no conflicts of interest. EDAT- 2021/01/25 06:00 MHDA- 2021/04/07 06:00 CRDT- 2021/01/24 20:33 PHST- 2020/08/12 00:00 [received] PHST- 2020/12/18 00:00 [revised] PHST- 2021/01/20 00:00 [accepted] PHST- 2021/01/25 06:00 [pubmed] PHST- 2021/04/07 06:00 [medline] PHST- 2021/01/24 20:33 [entrez] AID - S0026-0495(21)00010-X [pii] AID - 10.1016/j.metabol.2021.154710 [doi] PST - ppublish SO - Metabolism. 2021 Apr;117:154710. doi: 10.1016/j.metabol.2021.154710. Epub 2021 Jan 22.