Song Ren1, Longfei Pan2, Linqing Yang3, Zequn Niu4, Liming Wang4, Hui Feng4, Miao Yuan4. 1. Department of Geriatric Digestive Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, PR China. 2. Department of Emergency Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, PR China. Electronic address: panlonf@yeah.net. 3. Department of Nursing, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, PR China. 4. Department of Emergency Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, PR China.
Abstract
AIMS: Acute pancreatitis (AP) is an inflammatory disease of the pancreas that may affect local tissues or remote organ systems, while severe acute pancreatitis (SAP) is a life-threatening disorder associated with multiple organ failure. In this investigation, we set about to determine whether microRNA-29a-3p (miR-29a-3p) carried by mesenchymal stem cell (MSCs)-derived extracellular vesicles (EVs) affects the myocardial injury during SAP. MAIN METHODS: EVs were isolated from MSCs of rat bone marrow by differential centrifugation. An SAP rat model was developed and treated with MSCs-EVs and/or alteration of miR-29a-3p and HMGB1 expression, followed by assessment of the rats' cardiac function and inflammation. Next, cardiomyocytes H9C2 were co-cultured with MSC-EVs and internalization of EVs was evaluated, followed by evaluation of whether EVs could transmit miR-29a-3p cargos into H9C2 cells and affect their biological functions. KEY FINDINGS: EVs derived from MSCs were observed to protect against SAP-induced myocardial injury. In SAP-induced rats, miR-29a-3p was under-expressed in myocardial tissues. In addition, we also confirmed that miR-29a-3p could be transferred into the H9C2 cardiomyocytes by MSC-derived EVs, which downregulated the expression of inflammatory markers and improve cardiac function to attenuate myocardial injury. Furthermore, miR-29a-3p inhibited the expression of HMGB1 to downregulate TLR4 expression and further inactivate the Akt signaling pathway. SIGNIFICANCE: These findings support the cardioprotective action of miR-29a-3p transmitted by MSCs-derived EVs in SAP-induced myocardial injury via downregulation of the HMGB1/TLR4/Akt axis, highlighting a promising target for the EV-based therapy for SAP.
AIMS: Acute pancreatitis (AP) is an inflammatory disease of the pancreas that may affect local tissues or remote organ systems, while severe acute pancreatitis (SAP) is a life-threatening disorder associated with multiple organ failure. In this investigation, we set about to determine whether microRNA-29a-3p (miR-29a-3p) carried by mesenchymal stem cell (MSCs)-derived extracellular vesicles (EVs) affects the myocardial injury during SAP. MAIN METHODS: EVs were isolated from MSCs of rat bone marrow by differential centrifugation. An SAPrat model was developed and treated with MSCs-EVs and/or alteration of miR-29a-3p and HMGB1 expression, followed by assessment of the rats' cardiac function and inflammation. Next, cardiomyocytes H9C2 were co-cultured with MSC-EVs and internalization of EVs was evaluated, followed by evaluation of whether EVs could transmit miR-29a-3p cargos into H9C2 cells and affect their biological functions. KEY FINDINGS: EVs derived from MSCs were observed to protect against SAP-induced myocardial injury. In SAP-induced rats, miR-29a-3p was under-expressed in myocardial tissues. In addition, we also confirmed that miR-29a-3p could be transferred into the H9C2 cardiomyocytes by MSC-derived EVs, which downregulated the expression of inflammatory markers and improve cardiac function to attenuate myocardial injury. Furthermore, miR-29a-3p inhibited the expression of HMGB1 to downregulate TLR4 expression and further inactivate the Akt signaling pathway. SIGNIFICANCE: These findings support the cardioprotective action of miR-29a-3p transmitted by MSCs-derived EVs in SAP-induced myocardial injury via downregulation of the HMGB1/TLR4/Akt axis, highlighting a promising target for the EV-based therapy for SAP.