Abstract P3140: Targeting Of Kinin B1r/il-6 Signaling Prevents Microvascular Leakage And Mitochondrial Dysfunction In Sepsis Induced Heart Failure

Abstract

Introduction: Cardiovascular dysfunction is a major complication of severe sepsis. Microvascular leakage and mitochondrial dysfunction during sepsis are critically involved in heart failure. However, the underlying mechanisms between cardiac microvascular barrier function and sepsis-induced heart failure are not well studied. Kinin B1 receptor (B1R) regulates inflammation and induces capillary leakage. Previous findings from our lab also revealed an increase in B1R serum level in both septic patients and animal models within 24 hours. Hypothesis: We hypothesized that treatment with B1R antagonist protects against sepsis-induced microvascular leakage and mitochondrial dysfunction. Methods and Results: To address the hypothesis, we pre-treated WT male mice with either vehicle (control) or a specific B1R antagonist B6929 via subcutaneous injection, then subjected them to 40% cecal ligation and puncture (CLP) to induce polymicrobial sepsis. Echocardiographic analysis revealed an early cardioprotective effect of B1R inhibition, as evidenced by the improvement of EF%, FS%, and cardiac output in mice pre-treated with B1R antagonist (n=6-8, p<0.01) at 4-6 hours post-CLP. Furthermore, mitochondrial H 2 O 2 measurement of the freshly isolated cardiac mitochondria from CLP-induced septic mice also showed that B1R inhibition partially abolished the production of H 2 O 2 . The opening of mPTP was also reduced with B1R antagonist treatment. In vivo cardiac vascular permeability assessed using the Miles assay further demonstrated that B1R inhibition prevented sepsis-induced cardiac microvascular leakage and edema. Similar improvements were also observed in the liver and kidney. Interestingly,B1R antagonist treatment abolished CLP-induced serum level of IL-6 by 70%. In in-vitro study, B1R antagonist treatment inhibited LPS-induced IL-6 expressions in human cardiac microvacuolar endothelial cells (HCMECs). Finally, ECIS based analysis demonstrated that IL-6 deletion using either siRNA or B1R antagonist treatment rescued LPS-induced endothelial barrier leakage. Conclusions: Our findings suggest that targeting B1R via IL-6 may be a novel therapeutic approach for the treatment of sepsis-associated cardiovascular disease.