Platelet-derived extracellular vesicles encapsulate microRNA-34c-5p to ameliorate inflammatory response of coronary artery endothelial cells via PODXL-mediated P38 MAPK signaling pathway

• Published in: Nutrition, metabolism, and cardiovascular diseases Vol. 32; no. 10; pp. 2424 - 2438
• Main Authors: Bai, Xuetao, Zhang, Hao, Li, Zhiguo, Chen, Ou, He, Hengpeng, Jia, Xiukun, Zou, Lijuan
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.10.2022
• Subjects: animal models; Atherosclerosis; coculture; coronary artery disease; coronary vessels; death; Extracellular vesicles; Human coronary artery endothelial cells; humans; Inflammation; interleukin-6; loss-of-function mutation; low density lipoprotein; metabolism; microRNA; microRNA-34c-5p; mitogen-activated protein kinase; necrosis; neoplasms; nutrition; oxidation; P38 MAPK pathway; pathophysiology; Platelet; Human coronary artery endothelial cells; Platelet; Atherosclerosis; Extracellular vesicles; microRNA-34c-5p; Inflammation; P38 MAPK pathway
• ISSN: 0939-4753; 1590-3729; 1590-3729
• DOI: 10.1016/j.numecd.2022.06.013

Low-grade chronic inflammation was reported to serve as a distinctive pathophysiologic feature of coronary artery disease (CAD), the leading cause of death around the world. Herein, the current study aimed to explore whether and how microRNA-34c-5p (miR-34c-5p), a miRNA enriched in extracellular vesicles (EVs) originated from the activated platelet (PLT-EVs), affects the inflammation of human coronary artery endothelial cells (HCAECs). HCAECs were established as an in vitro cell model using oxidized low-density lipoprotein (ox-LDL). miR-34c-5p, an abundant miRNA in PLT-EVs, can be transferred to HCAECs and target PODXL by binding to its 3′UTR. Gain- and loss-of-function experiments of miR-34c-5p and podocalyxin (PODXL) were performed in ox-LDL-induced HCAECs. Subsequently, HCAECs were subjected to co-culture with PLT-EVs, followed by detection of the expression patterns of key pro-inflammatory factors. Either miR-34c-5p mimic or PLT-EVs harboring miR-34c-5p attenuated the ox-LDL-evoked inflammation in HCAECs by suppressing interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α). By blocking the P38 MAPK signaling pathway, miR-34c-5p-mediated depletion of PODXL contributed to protection against ox-LDL-induced inflammation. In vitro findings were further validated by findings observed in ApoE knock-out mice. Additionally, miR-34c-5p in PLT-EVs showed an athero-protective role in the murine model. Altogether, our findings highlighted that miR-34c-5p in PLT-EVs could alleviate inflammation response in HCAECs by targeting PODXL and inactivation of the P38 MAPK signaling pathway. •miR-34c-5p is poorly expressed in ox-LDL-treated HCAECs but enriched in activated PLT-EVs.•PLT-EVs transmit miR-34c-5p to protect against ox-LDL-induced inflammation in HCAECs.•PODXL is a target gene of miR-34c-5p.•PLT-EV miR-34c-5p alleviates inflammation via inhibition of the PODXL/P38 MAPK axis.•This study provides novel insights for EV-based individualized therapies coronary artery disease.