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Attenuation of Cardiac Dysfunction in Polymicrobial Sepsis by MicroRNA-146a Is Mediated via Targeting of IRAK1 and
Ming Gao1, Xiaohui Wang1, Xia Zhang1
1Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614;
Abstract:
Cardiac dysfunction is a major consequence of sepsis/septic shock and contributes to the high mortality of sepsis. Innate and inflammatory responses mediated by TLRs play a critical role in sepsis-induced cardiac dysfunction. MicroRNA-146 (miR-146) was first identified as a negative regulator in innate immune and inflammatory responses induced by LPS. This study examined whether miR-146a will have a protective effect on sepsis-induced cardiac dysfunction. Lentivirus-expressing miR-146a (LmiR-146a) or lentivirus-expressing scrambled miR (LmiR-control) was delivered into the myocardium via the right carotid artery. Seven days after transfection, mice were subjected to cecal ligation and puncture (CLP). Untransfected mice were also subjected to CLP-induced sepsis. Cardiac function was examined by echocardiography before and 6 h after CLP. In vitro studies showed that increased miR-146a levels suppress LPS-induced IκBα phosphorylation and inflammatory cytokine production in both H9C2 cardiomyocytes and J774 macrophages. In vivo transfection of LmiR-146a attenuated sepsis-induced cardiac dysfunction. The values for percent ejection fraction and percent fractional shortening in LmiR-146a-transfected CLP mice were significantly greater than in untransfected CLP control. LmiR-146a transfection prevented sepsis-induced NF-κB activity, suppressed IRAK and TRAF6 expression in the myocardium, and attenuated sepsis-induced inflammatory cytokine production in both plasma and peritoneal fluid. In addition, LmiR-146a transfection decreased sepsis-induced infiltration of neutrophils and macrophages into the myocardium. LmiR-146a can also transfect macrophages in the periphery. We conclude that miR-146a attenuates sepsis-induced cardiac dysfunction by preventing NF-κB activation, inflammatory cell infiltration, and inflammatory cytokine production via targeting of IRAK and TRAF6 in both cardiomyocytes and inflammatory monocytic cells.
Insights
MicroRNA-146a protects against sepsis-induced cardiac dysfunction by suppressing inflammation and NF-κB activation. This study shows miR-146a targets IRAK and TRAF6, reducing inflammatory cell infiltration and improving heart function in sepsis models.
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Medicine
Background:
- Sepsis-induced cardiac dysfunction is a significant cause of mortality.
- Toll-like receptor (TLR)-mediated inflammatory responses critically contribute to sepsis-related heart problems.
- MicroRNA-146a (miR-146a) is known to regulate innate immune and inflammatory pathways.
Purpose of the Study:
- To investigate the protective role of miR-146a against sepsis-induced cardiac dysfunction.
- To elucidate the molecular mechanisms underlying miR-146a's effects in sepsis.
- To assess miR-146a's impact on inflammatory responses in cardiac and immune cells.
Main Methods:
- Delivery of lentivirus-expressing miR-146a (LmiR-146a) or control into mouse myocardium.
- Induction of sepsis via cecal ligation and puncture (CLP) in mice.
- Assessment of cardiac function using echocardiography, analysis of NF-κB activity, inflammatory markers, and immune cell infiltration.
Main Results:
- LmiR-146a transfection significantly improved cardiac function (ejection fraction, fractional shortening) in CLP mice.
- miR-146a suppressed LPS-induced inflammatory responses in cardiomyocytes and macrophages in vitro.
- In vivo, LmiR-146a attenuated cardiac NF-κB activation, reduced IRAK/TRAF6 expression, decreased inflammatory cytokine levels, and inhibited neutrophil/macrophage infiltration in the myocardium.
Conclusions:
- miR-146a exhibits a protective effect against sepsis-induced cardiac dysfunction.
- The mechanism involves the suppression of NF-κB activation, inflammatory cell infiltration, and cytokine production by targeting IRAK and TRAF6.
- miR-146a holds therapeutic potential for managing sepsis-related heart complications.
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