Abstract

Background: Endotoxemic/septic, cardiac dysfunction occurs frequently in elderly patients undergoing major surgery and contributes to post-surgery morbidity and mortality. This study evaluated the effect of aging on cardiac functional recovery following endotoxemia and explored therapeutic approaches for promotion of the recovery. Methods & Results: A small dose of endotoxin (0.5 mg/kg, iv) was administered to young adult (3-4 months) and old (18-22 months) mice with or without subsequent treatment with recombinant interleukin-37 (IL-37, 50 µg/kg, iv) or recombinant Klotho (10 µg/kg, iv). Cardiac function was analyzed using a microcatheter at 24, 48 and 96 h following administration of endotoxin. Myocardial levels of Klotho, ICAM-1 and IL-6 were determined by immunoblotting and ELISA. Compared to young adult endotoxemic mice, old endotoxemic mice had worse cardiac dysfunction accompanied by greater myocardial levels of ICAM-1 and IL-6 at each time point and failed to fully recover cardiac function by 96 h. The exacerbated and prolonged myocardial inflammation and cardiac dysfunction in old endotoxemic mice were associated with lower myocardial Klotho level and its further reduction by endotoxemia. Interestingly, recombinant IL-37 up-regulated myocardial Klotho level in old mice with or without endotoxemia, and treatment of old endotoxemic mice with IL-37 improved myocardial inflammation resolution and cardiac functional recovery. Similarly, recombinant Klotho suppressed myocardial inflammatory response and promoted inflammation resolution in old endotoxemic mice, leading to complete recovery of cardiac function by 96 h. Conclusion: Myocardial Klotho insufficiency in old mice exacerbates myocardial inflammatory response, impairs inflammation resolution and hinders cardiac functional recovery. IL37 is capable of up-regulating myocardial Klotho level to promote myocardial inflammation resolution and cardiac functional recovery in old endotoxemic mice.