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


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.
Department of Surgery, University of Colorado Denver, Aurora, USA.|Department of Geriatric Cardiology, PLA General Hospital, Beijing, China.
Haipeng
H
Hui
Department of Surgery, University of Colorado Denver, Aurora, USA.
Yufeng
Y
Zhai
Department of Surgery, University of Colorado Denver, Aurora, USA.
Lihua
L
Ao
Department of Surgery, University of Colorado Denver, Aurora, USA.
Joseph C
JC
Cleveland
Department of Geriatric Cardiology, PLA General Hospital, Beijing, China.
Hongbin
H
Liu
Department of Surgery, University of Colorado Denver, Aurora, USA.
David A
DA
Fullerton
Department of Surgery, University of Colorado Denver, Aurora, USA.
Xianzhong
X
Meng
D000375:Aging; D000818:Animals; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D019446:Endotoxemia / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D004797:Enzyme-Linked Immunosorbent Assay; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D015151:Immunoblotting; D007249:Inflammation / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D000090265:Klotho Proteins; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology
D016207:Cytokines; D018840:HSP70 Heat-Shock Proteins; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D005966:Glucuronidase; D000090265:Klotho Proteins
Klotho; aging; endotoxemic cardiac dysfunction; heat shock protein; inflammation