Beclin-1-Dependent Autophagy Protects the Heart During Sepsis

Abstract

<div class="section"> <a class="named-anchor" id="S1"> <!-- named anchor --> </a> <h5 class="section-title" id="d528734e269">Background:</h5> <p id="P2">Cardiac dysfunction is a major component of sepsis-induced multi-organ failure in critical care units. Changes in cardiac autophagy and its role during sepsis pathogenesis have not been clearly defined. Targeted autophagy-based therapeutic approaches for sepsis are not yet developed. </p> </div><div class="section"> <a class="named-anchor" id="S2"> <!-- named anchor --> </a> <h5 class="section-title" id="d528734e274">Methods:</h5> <p id="P3">Beclin-1-dependent autophagy in the heart during sepsis and the potential therapeutic benefit of targeting this pathway were investigated in a mouse model of lipopolysaccharide (LPS)-induced sepsis. </p> </div><div class="section"> <a class="named-anchor" id="S3"> <!-- named anchor --> </a> <h5 class="section-title" id="d528734e279">Results:</h5> <p id="P4">LPS induced a dose-dependent increase in autophagy at low doses, followed by a decline that was in conjunction with mTOR activation at high doses. Cardiac-specific overexpression of Beclin-1 promoted autophagy, suppressed mTOR signaling, improved cardiac function, and alleviated inflammation and fibrosis after LPS challenge. Haplosufficiency for <i>beclin 1</i> resulted in opposite effects. Beclin-1 also protected mitochondria, reduced the release of mitochondrial DAMPs, and promoted mitophagy via PINK1-Parkin but not adaptor proteins in response to LPS. Injection of a cell-permeable Tat-Beclin-1 peptide to activate autophagy improved cardiac function, attenuated inflammation, and rescued the phenotypes caused by <i>beclin 1</i> deficiency in LPS-challenged mice. </p> </div><div class="section"> <a class="named-anchor" id="S4"> <!-- named anchor --> </a> <h5 class="section-title" id="d528734e290">Conclusions:</h5> <p id="P5">These results suggest that Beclin-1 protects the heart during sepsis and that the targeted induction of Beclin-1 signaling may have important therapeutic potential. </p> </div>