MicroRNA-125b Prevents Cardiac Dysfunction in Polymicrobial Sepsis by Targeting TRAF6-Mediated Nuclear Factor κB Activation and p53-Mediated Apoptotic Signaling.
BACKGROUND
This study examined the effect of microRNA-125b (miR-125b) on sepsis-induced cardiac dysfunction.


METHODS
Mouse hearts were transfected with lentivirus expressing miR-125b (LmiR-125b) 7 days before cecal ligation and puncture (CLP)-induced sepsis. Cardiac function was examined by echocardiography before and 6 hours after CLP (n = 6/group). Survival was monitored following CLP-induced sepsis (n = 12/group).


RESULTS
LmiR-125b transfection significantly attenuated cardiac dysfunction due to CLP-induced sepsis. Fractional shortening and ejection fraction values were significantly (P < .05) higher in the LmiR-125b-treated CLP group than in the untreated CLP group. Survival outcome in LmiR-125b-transfected septic mice was markedly improved, compared with mice with CLP-induced sepsis. Transfection of LmiR-125b into the heart significantly suppressed the expression of ICAM-1 and VCAM-1, decreased the accumulation of macrophages and neutrophils in the myocardium, and decreased serum levels of tumor necrosis factor α and interleukin 1β by targeting tumor necrosis factor receptor-associated factor 6 (TRAF6)-mediated nuclear factor κB (NF-κB) activation. In addition, sepsis-induced myocardial apoptosis was markedly attenuated by LmiR-125b transfection through suppression of p53, Bax, and Bak1 expression. In vitro transfection of endothelial cells with miR-125b mimics attenuate LPS-induced ICAM-1 and VCAM-1 expression by suppressing TRAF6 and NF-κB activation.


CONCLUSIONS
Increased myocardial miR-125b expression attenuates sepsis-induced cardiac dysfunction and improves survival. miR-125b may be a target for septic cardiomyopathy.
Department of Surgery.|Department of Geriatrics, First Affiliated Hospital of Nanjing Medical University.
He
H
Ma
Department of Surgery.
Xiaohui
X
Wang
Department of Surgery.|Center of Excellence in Inflammation, Infectious Disease, and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City.
Tuanzhu
T
Ha
Department of Surgery.
Ming
M
Gao
Department of Geriatrics, First Affiliated Hospital of Nanjing Medical University.
Li
L
Liu
Department of Internal Medicine, Third Affiliated Hospital of Harbin Medical University, Harbin, China.
Ruitao
R
Wang
Department of Internal Medicine, Third Affiliated Hospital of Harbin Medical University, Harbin, China.
Kaijiang
K
Yu
Department of Biometry and Medical Computing.|Center of Excellence in Inflammation, Infectious Disease, and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City.
John H
JH
Kalbfleisch
Department of Surgery.|Center of Excellence in Inflammation, Infectious Disease, and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City.
Race L
RL
Kao
Department of Surgery.|Center of Excellence in Inflammation, Infectious Disease, and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City.
David L
DL
Williams
Department of Surgery.|Center of Excellence in Inflammation, Infectious Disease, and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City.
Chuanfu
C
Li
D000818:Animals; D060085:Coinfection / Q000150:complications / Q000473:pathology*; D004195:Disease Models, Animal; D004452:Echocardiography; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D009206:Myocardium / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D018805:Sepsis / Q000150:complications / Q000473:pathology*; D015398:Signal Transduction; D016019:Survival Analysis; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*
D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6
NF-κB; TRAF6; apoptosis; cardiac function; microRNA-125b; sepsis
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