Yufeng Zhai, MS
Senior Research Assistant
University of Colorado Anschutz Medical Campus
Aurora, Colorado, United States
Disclosure information not submitted.
Lihua Ao, BS
Senior Research Assistant
University of Colorado Anschutz Medical Campus
Aurora, Colorado, United States
Disclosure information not submitted.
David Fullerton, MD
Professor and Division Chief
University of Colorado Anschutz Medical Campus
Aurora, Colorado, United States
Disclosure information not submitted.
Xianzhong Meng, MD, PhD
Professor and Director of Research
University of Colorado Anschutz Medical Campus
Aurora, Colorado, United States
Disclosure information not submitted.
Title: Klotho protects against aging-related cardiac dysfunction caused by sepsis
Introduction: Cardiac dysfunction is common in sepsis and exacerbates the mortality of sepsis patients. The elderly with sepsis frequently experiences worse cardiac dysfunction compared with adult patients. However, the underlying mechanism remains unclear. Old mice display an aging-related phenotype of sepsis comparable to that of old people. In the present study, we tested the hypotheses that aging-associated Klotho insufficiency exacerbates cardiac dysfunction during sepsis and that anti-inflammatory approach would reverse the aging phenotype of septic cardiac dysfunction by up-regulation of myocardial Klotho expression.
Methods: Male adult (4-6 months) and old (18-21 months) C57BL/6 mice were subjected to moderate sepsis by cecal ligation and puncture (CLP; 1 puncture with a 27G needle). Two additional groups of old mice were treated with recombinant Klotho (10 µg/kg, iv) or recombinant IL-37 (50 µg/kg, iv) at 1 h after CLP. Left ventricle (LV) function was assessed with a pressure-volume microcatheter at 2 and 4 days after CLP. Myocardial levels of Klotho were assessed by immunoblotting.
Results: CLP reduced cardiac function in adult mice. However, identical CLP caused more severe cardiac dysfunction and resulted in a high mortality (46%) in old mice. The exacerbated septic cardiac dysfunction in old mice was associated with lower levels of Klotho in the heart. Administration of recombinant Klotho markedly improved cardiac function and reduced mortality in old mice following CLP. Interestingly, treatment of old mice with anti-inflammatory cytokine IL-37 up-regulated the level of Klotho in the myocardium of old mice. More importantly, IL-37 treatment markedly improved cardiac function and reduced mortality in old septic mice.
Conclusion: Old mice display more severe cardiac dysfunction and higher mortality following moderate sepsis. Klotho insufficiency in the heart contributes to the mechanism underlying the aging phenotype of septic cardiac dysfunction. Anti-inflammatory cytokine IL-37 can reverse this aging phenotype and may have therapeutic potential for cardioprotection in the elderly affected by sepsis.