Oncotarget

Research Papers:

Klotho suppresses the inflammatory responses and ameliorates cardiac dysfunction in aging endotoxemic mice

Haipeng Hui _, Yufeng Zhai, Lihua Ao, Joseph C. Cleveland Jr, Hongbin Liu, David A. Fullerton and Xianzhong Meng

PDF  |  HTML  |  How to cite

Oncotarget. 2017; 8:15663-15676. https://doi.org/10.18632/oncotarget.14933

Metrics: PDF 2387 views  |   HTML 3498 views  |   ?  


Abstract

Haipeng Hui1,2,*, Yufeng Zhai1,*, Lihua Ao1, Joseph C. Cleveland Jr1, Hongbin Liu2, David A. Fullerton1, Xianzhong Meng1

1Department of Surgery, University of Colorado Denver, Aurora, USA

2Department of Geriatric Cardiology, PLA General Hospital, Beijing, China

*These authors have contributed equally to this work

Correspondence to:

Xianzhong Meng, email: [email protected]

Keywords: aging, endotoxemic cardiac dysfunction, inflammation, Klotho, heat shock protein

Received: September 22, 2016    Accepted: December 27, 2016    Published: February 01, 2017

ABSTRACT

Background: Aging augments endotoxemic cardiac dysfunction, but the mechanism remains unclear. Anti-aging protein Klotho has been found to modulate tissue inflammatory responses. We tested the hypothesis that a reduced Klotho level in aging heart plays a role in the augmented endotoxemic cardiac dysfunction.

Materials and Methods: Endotoxin (0.5 mg/kg, iv) was injected to adults (4-6 months) and aging (18-20 months) C57BL/6 mice. Recombinant Klotho (10 μg/kg, iv) was administered to a group of aging mice after endotoxin injection. Cardiac function was analyzed using a microcatheter at 24 and 48 h after endotoxin administration. Myocardial levels of Klotho and heat shock protein 70 (HSP70) were determined by immunoblotting, and plasma and myocardial cytokines were analyzed using ELISA.

Results: More severe cardiac dysfunction in aging mice were accompanied by greater cytokine levels in the plasma and myocardium. Klotho was detected in the myocardial tissue. Klotho levels were lower in aging hearts and were further reduced during endotoxemia. Myocardial HSP70 levels were correlated with Klotho levels. Recombinant Klotho increased myocardial HSP70, inhibited NF-κB activation, reduced cytokine levels, and improved cardiac function in aging endotoxemic mice. Delivery of HSP70 into cultured macrophages suppressed endotoxin-induced NF-κB activation.

Conclusions: Aging-related augmentation of inflammatory responses and cardiac dysfunction is associated with relative Klotho deficiency. Post-treatment with recombinant Klotho suppresses the inflammatory responses and improves cardiac function in aging endotoxemic mice. Klotho modulates HSP70 levels and HSP70 appears to be involved in the anti-inflammatory mechanism of Klotho. Klotho may have therapeutic potential in amelioration of aging-related endotoxemic cardiac dysfunction.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 14933