Abstract MP224: IL-10 Protects The Heart From Late Phage Cardiac Inflammation Associated With Intestinal Permeability Following Transaortic Constriction

Abstract

Introduction: Impaired intestinal permeability is known to augment cardiac dysfunction. Though the cardioprotective role of IL-10 is known in early phase cardiac inflammation, following transaortic constriction (TAC), its role in alleviating late phase cardiac inflammation associated with intestinal permeability is not known. Hypothesis: We hypothesized that IL-10 reduces late-phase cardiac inflammation by minimizing intestinal permeability and systemic reduction of pathogen-associated molecular pattern (PAMP), which ultimately improve cardiac function. Methods: WT and IL-10 KO mice (n=6 in each group) were subjected to TAC or sham surgery, and echocardiography was performed to evaluate cardiac function for up to 56 days. Heart and intestine were collected to evaluate inflammation (RT-qPCR), immune cell infiltration (flow cytometry), and intestinal permeability (WB and immunohistochemistry). Blood was collected to quantify the level of peptidoglycan (PGN, a PAMP) and other bacterial metabolites. The effect of PGN on mitochondrial function was evaluated in neonatal rat ventricular myocyte (NRVM). Results: Cardiac functions were significantly reduced in IL10-KO mice, following TAC till 56 days. Furthermore, exacerbated inflammation was observed both at early phase (within 14 days) and late phase (around 56 days) in IL-10 KO TAC mice as compare to the WT counterpart. Interestingly, early cardiac inflammation coincided with immune cell infiltration into the intestine of IL-10 KO mice following TAC. Enhanced inflammatory immune cells homing to the intestine following TAC led to gut dysbiosis (16S RNA sequencing) which ultimately caused impaired gut wall permeability in the IL-10 KO mice as compared to the WT mice. Further, plasma PGN level was significantly increased in IL-10 KO mice following TAC. Finally, our cardiotoxicity array in neonatal rat cardiomyocytes following PGN treatment showed altered expression of proteins which are involved in the regulation of mitochondrial function and cardiac contractility. Conclusion: IL-10 plays an important role in limiting late phase cardiac inflammation by reducing intestinal permeability and systemic increase in PGN which induce inflammation and mitochondrial dysfunction in cardiac muscle.