Up-regulation of Myocardial Klotho Expression to Promote Cardiac Functional Recovery in Old Mice following Endotoxemia

OBJECTIVE: Endotoxemic cardiac dysfunction contributes to greater morbidity and mortality in elderly patients with sepsis. This study tested the hypothesis that Klotho insufficiency in aging heart exaggerates and prolongs myocardial inflammation to hinder cardiac function recovery following endotoxemia. METHODS: 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 24, 48 and 96 h later. Myocardial levels of Klotho, ICAM-1, VCAM-1 and IL-6 were determined by immunoblotting and ELISA. RESULTS: In comparison to young adult mice, old mice had worse cardiac dysfunction accompanied by greater myocardial levels of ICAM-1, VCAM-1 and IL-6 at each time point following endotoxemia and failed to fully recover cardiac function by 96 h. The exacerbated myocardial inflammation and cardiac dysfunction were associated with endotoxemia-caused further reduction of lower myocardial Klotho level in old mice. Recombinant IL-37 promoted inflammation resolution and cardiac functional recovery in old mice. Interestingly, recombinant IL-37 markedly up-regulated myocardial Klotho levels in old mice with or without endotoxemia. 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 endotoxemic mice exacerbates myocardial inflammatory response, impairs inflammation resolution and thereby hinders cardiac functional recovery. IL-37 is capable of up-regulating myocardial Klotho expression to improve cardiac functional recovery in old endotoxemic mice.