MicroRNA-155 attenuates late sepsis-induced cardiac dysfunction through JNK and β-arrestin 2

Abstract

// Yu Zhou 1, 2 , Yan Song 3, 1 , Zahir Shaikh 1 , Hui Li 1 , Haiju Zhang 1 , Yi Caudle 1 , Shouhua Zheng 4 , Hui Yan 1 , Dan Hu 2 , Charles Stuart 1 and Deling Yin 1 1 Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA 2 Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China 3 Department of Vascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China 4 Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China Correspondence to: Deling Yin, email: [e-mail] Keywords: microRNA-155, late sepsis, cardiac dysfunction, β-arrestin 2, inflammatory Received: February 09, 2017      Accepted: April 19, 2017      Published: May 04, 2017 ABSTRACT Cardiac dysfunction is correlated with detrimental prognosis of sepsis and contributes to a high risk of mortality. After an initial hyperinflammatory reaction, most patients enter a protracted state of immunosuppression (late sepsis) that alters both innate and adaptive immunity. The changes of cardiac function in late sepsis are not yet known. MicroRNA-155 (miR-155) is previously found to play important roles in both regulations of immune activation and cardiac function. In this study, C57BL/6 mice were operated to develop into early and late sepsis phases, and miR-155 mimic was injected through the tail vein 48 h after cecal ligation and puncture (CLP). The effect of miR-155 on CLP-induced cardiac dysfunction was explored in late sepsis. We found that increased expression of miR-155 in the myocardium protected against cardiac dysfunction in late sepsis evidenced by attenuating sepsis-reduced cardiac output and enhancing left ventricular systolic function. We also observed that miR-155 markedly reduced the infiltration of macrophages and neutrophils into the myocardium and attenuated the inflammatory response via suppression of JNK signaling pathway. Moreover, overexpression of β-arrestin 2 (Arrb2) exacerbated the mice mortality and immunosuppression in late sepsis. Furthermore, transfection of miR-155 mimic reduced Arrb2 expression, and then restored immunocompetence and improved survival in late septic mice. We conclude that increased miR-155 expression through systemic administration of miR-155 mimic attenuates cardiac dysfunction and improves late sepsis survival by targeting JNK associated inflammatory signaling and Arrb2 mediated immunosuppression.