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Cardiac oxidative stress and inflammation play a key role in the pathogenesis of diabetic cardiomyopathy (DCM). The anti-aging protein Klotho has been found to protect cells from oxidative stress and inflammation. The current study aimed to explore the cardioprotective effects of Klotho on DCM and the underlying mechanisms.
H9c2 cardiomyocytes were exposed to 33 mM glucose in the presence or absence of Klotho. In addition, we established a type 1 diabetic mouse model to assess the protective effect of Klotho in vivo.
Klotho pretreatment effectively suppressed high glucose-induced inflammation, reactive oxygen species, apoptosis, mitochondrial dysfunction, hypertrophy and fibrosis in H9c2 cells. In STZ-induced type 1 diabetic mice, intraperitoneal injection of Klotho at 0.01 mg/kg per 48 h for 3 months completely suppressed cardiac inflammatory cytokines and oxidative stress and prevented cardiac cell death and remodeling, which subsequently improved cardiac dysfunction without affecting hyperglycemia. This study revealed that Klotho may exert its protective effects by augmenting nuclear factor E2-related factor 2 (Nrf2) expression and inactivating (nuclear factor κB) NF-κB activation both in vitro and in vivo.
This work demonstrated for the first time that the anti-aging protein Klotho may have great potential for use in treating DCM by inhibiting oxidative stress and inflammation. We also demonstrated the critical roles of the Nrf2 and NF-κB pathways in diabetes-stimulated cardiac injuries and indicated that they may be key therapeutic targets for diabetic complications.