Intermedin(1-53) Protects Cardiac Fibroblasts by Inhibiting NLRP3 Inflammasome Activation During Sepsis

Sepsis is a disease that occurs as a result of systemic inflammatory response syndrome (SIRS) in response to an infection, contributing to multiple organ dysfunction and a high mortality rate. Interleukin-l beta (IL-1 beta) is a cytokine that plays critical roles in inflammation and cardiac dysfunction during severe sepsis. Intermedin(1-53) (IMD1-53) has been recently discovered to possess potential endogenous anti-inflammatory and strong cardiovascular protective effects. To investigate whether IMD1-53 can inhibit the NLRP3/caspase-1/IL-1 beta pathway to alleviate cardiac injury and rescue heart function, sepsis was induced in vivo by caecal ligation and puncture (CLP) surgery, and lipopolysaccharides were used as septic stressors for cardiac fibroblasts (CFs) in vitro. The expressions of IMD1-53 receptors in sepsis rat heart were increased. After IMD1-53 treatment, inflammation caused by sepsis in vivo was greatly reduced, as shown by the downregulation of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), nucleotide-binding domain and leucine-rich repeat containing family, pyrin containing 3 (NLRP3), pro-IL-1 beta, caspase 1, and nuclear translocation of nuclear factor-kappa B (NF-kB) protein levels. In addition, cardiac function was significantly improved and mean arterial blood pressure (MABP) increased by 34.8% (P < 0.05) which almost back to normal. Surprisingly, IMD1-53 inhibited cell apoptosis, as caspase 3 activity and Bax expression was significantly reduced in the heart upon IMD1-53 treatment. IMD1-53 abolished the upregulation of ASC, NLRP3, and caspase 1 protein levels in CFs induced by lipopolysaccharide (LPS). IMD1-53 increased cell survival rates and inhibited IL-1 beta production in the cell culture medium. IMD1-53 can protect against inflammation and heart injury during sepsis via attenuating the NLRP3/caspase-1/IL-1 beta pathway.