Cardiovascular dysfunction is a major complication associated with sepsis induced morbidity and mortality. Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection4. The recent Sepsis-3 guidelines recommend that persistence of serum lactate >2 mmol/L, despite adequate fluid resuscitation, should be included as a new criteria when clinically defining septic shock. Clinical data shows that lactate levels correlate strongly and positively with severity, morbidity and mortality in sepsis. Although lactate is a well-accepted biomarker of sepsis, recent evidence indicates that lactate may play a pathophysiological role in sepsis induced cardiovascular dysfunction. We have made a novel discovery that high levels of lactate directly cause vascular dysfunction and cardiomyopathy in polymicrobial sepsis. Specifically, we discovered that elevated serum lactate levels in a mouse model of cecal ligation and puncture (CLP) sepsis significantly increased vascular permeability, worsened cardiomyopathy, and accelerated mortality. In contrast, inhibition of lactate production by suppression of hexokinase in glycolysis, significantly improved survival outcome and cardiac function in CLP sepsis. Importantly, our preliminary data shows that lactate significantly decreased cadherins junction protein (vascular endothelial cadherine, VE-cadherine) and tight junction protein-1 ZO-1 in the myocardium. VE- cadherin and ZO1 are important proteins for endothelial cell barrier function. We also found that lactate markedly stimulated yes associated protein (YAP) phosphorylation and induced YAP disassociated with VE- cadherin, resulting in VE-cadherin translocation from cell membrane into endosome/lysosome for degradation. Our findings suggest that high levels of lactate exerts deleterious effects on cardiovascular function during sepsis. The goals of this application are to decipher the cellular and molecular mechanisms of lactate mediated cardiovascular dysfunction during polymicrobial sepsis. Based on our novel findings, we hypothesize that “lactate is a novel endogenous effector which mediates cardiovascular dysfunction in sepsis by disassociation of VE-cadherin with YAP and promoting VE-cadherin translocation to endosomes/lysosomes, resulting in endothelial barrier dysfunction”. Specific aim 1. Investigate whether lactate mediates endothelial cell permeability via disassociation of YAP with VE-cadherin on cell membrane. In this aim, we will investigate whether lactate decreased YAP levels are mediated through activation of AMPK and LATS1/2 signaling. We will also investigate whether YAP plays an important role in the stabilization of VE-cadherin on cellular membrane in endothelial cells and regulates the expression of VE-cadherin and tight junction proteins. Specific aim 2. Define the role of lactate receptor, GPR81 in lactate induced vascular permeability during sepsis. In this aim, we will investigate whether lactate promoted V...