Angiotensin-converting enzyme inhibitors provide a protective effect on hypoxia-induced injury in human coronary artery endothelial cells via Nrf2 signaling and PLVAP

Article type: Research Article

Authors: Zhang, Qiubing^{a; b; 1} | Gou, Fang^{b; 1} | Shi, Ping^{b; 1} | Xu, Zhe^{b; 1} | Yan, Zhitao^b | He, Mingfang^b | Yin, Xiaohong^b | He, Yuanjun^b | Zhang, Jun^{c; *}

Affiliations: [a] Tianjin Medical University, Tianjin, China | [b] Department of Cardiology, Guang Yuan Central Hospital, Guang Yuan, China | [c] Department of Cardiology, Cangzhou Central Hospital, Tianjin Medical University, Cangzhou, China

Correspondence: [*] Corresponding author: Jun Zhang, Department of Cardiology, Cangzhou Central Hospital, Tianjin Medical University, No. 16 Xinhua West Road, Cangzhou 061000, China. Tel.: +86 15903177566; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: BACKGROUND:Angiotensin-converting enzyme inhibitors (ACEIs) were reported to protect from hypoxia-induced oxidative stress in coronary endothelial cells (CECs) after acute myocardial infarction (AMI). Nrf2 shows a protective effect in hypoxia-induced CECs after AMI. Plasmalemma vesicle-associated protein (PLVAP) plays a pivotal role in angiogenesis after AMI. AIM:To explore the protective effect of ACEIs and the involved mechanisms under hypoxia challenge. METHODS:Human coronary endothelial cells (HCAECs) were used to establish hypoxia-induced oxidative stress injury in vitro. Flow cytometry was used to evaluate the protective effect of ACEI on hypoxia conditions.ET-1, NO, ROS, and VEGF were detected by ELISA. HO-1, Nrf2, and Keap-1, the pivotal member in the Nrf2 signaling pathway, eNOS and PLVAP were detected in HEAECs treated with ACEI by immunofluorescence, qPCR, and western blotting. RESULTS:The hypoxia ACEI or Nrf2 agonist groups showed higher cell viability compared with the hypoxia control group at 24 (61.75±1.16 or 61.23±0.59 vs. 44.24±0.58, both P < 0.05) and 48 h (41.85±1.19 or 59.64±1.13 vs. 22.98±0.25, both P < 0.05). ACEI decreased the levels of ET-1 and ROS under hypoxia challenge at 24 and 48 h (all P < 0.05); ACEI increased the VEGF and NO levels (all P < 0.05). ACEI promoted the expression level of eNOS, HO-1, Nrf2 and PLVAP but inhibited Keap-1 expression at the mRNA and protein levels (all P < 0.05). Blockade of the Nrf2 signaling pathway significantly decreased the expression level of PLVAP. CONCLUSION:ACEI protects hypoxia-treated HEAECs by activating the Nrf2 signaling pathway and upregulating the expression of PLVAP.

Keywords: Acute myocardial infarction, angiotensin-converting enzyme inhibitor, nuclear factor erythroid 2 signaling pathway, human coronary endothelial cells, plasmalemma vesicle-associated protein

DOI: 10.3233/CH-232007

Journal: Clinical Hemorheology and Microcirculation, vol. Pre-press, no. Pre-press, pp. 1-30, 2024