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Klotho protects the heart from hyperglycemia-induced injury by inactivating ROS and NF-κB-mediated inflammation both in vitro and in vivo.
Biochim Biophys Acta Mol Basis Dis. 2018 Jan; 1864(1):238-251.BB

Abstract

Cardiac inflammation and oxidative stress play a key role in the pathogenesis of diabetic cardiomyopathy (DCM). The anti-aging protein Klotho has been found to protect cells from inflammation and oxidative stress. The current study aimed to explore the cardioprotective effects of Klotho on DCM and the underlying mechanisms. H9c2 cells and neonatal cardiomyocytes were incubated with 33mM glucose in the presence or absence of Klotho. Klotho pretreatment effectively inhibited high glucose-induced inflammation, ROS generation, apoptosis, mitochondrial dysfunction, fibrosis and hypertrophy in both H9c2 cells and neonatal cardiomyocytes. In STZ-induced type 1 diabetic mice, intraperitoneal injection of Klotho at 0.01mg/kg per 48h for 3months 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 erythroid 2-related factor 2 (Nrf2) expression and inactivating nuclear factor κB (NF-κB) activation both in vitro and in vivo. Thus, this work demonstrated for the first time that the anti-aging protein Klotho may be a potential therapeutic agent to treat 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.

Authors+Show Affiliations

Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, PR China; Key Laboratory of Assisted Circulation, Ministry of Health, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, PR China.Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, PR China.Department of Critical Care Medicine and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, PR China.Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510630, PR China.Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, PR China.Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, PR China.Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, PR China.Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, PR China; Key Laboratory of Assisted Circulation, Ministry of Health, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, PR China. Electronic address: wanglich@mail.sysu.edu.cn.Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, PR China; Key Laboratory of Assisted Circulation, Ministry of Health, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, PR China. Electronic address: liaoxinx@mail.sysu.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28982613

Citation

Guo, Yue, et al. "Klotho Protects the Heart From Hyperglycemia-induced Injury By Inactivating ROS and NF-κB-mediated Inflammation Both in Vitro and in Vivo." Biochimica Et Biophysica Acta. Molecular Basis of Disease, vol. 1864, no. 1, 2018, pp. 238-251.
Guo Y, Zhuang X, Huang Z, et al. Klotho protects the heart from hyperglycemia-induced injury by inactivating ROS and NF-κB-mediated inflammation both in vitro and in vivo. Biochim Biophys Acta Mol Basis Dis. 2018;1864(1):238-251.
Guo, Y., Zhuang, X., Huang, Z., Zou, J., Yang, D., Hu, X., Du, Z., Wang, L., & Liao, X. (2018). Klotho protects the heart from hyperglycemia-induced injury by inactivating ROS and NF-κB-mediated inflammation both in vitro and in vivo. Biochimica Et Biophysica Acta. Molecular Basis of Disease, 1864(1), 238-251. https://doi.org/10.1016/j.bbadis.2017.09.029
Guo Y, et al. Klotho Protects the Heart From Hyperglycemia-induced Injury By Inactivating ROS and NF-κB-mediated Inflammation Both in Vitro and in Vivo. Biochim Biophys Acta Mol Basis Dis. 2018;1864(1):238-251. PubMed PMID: 28982613.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Klotho protects the heart from hyperglycemia-induced injury by inactivating ROS and NF-κB-mediated inflammation both in vitro and in vivo. AU - Guo,Yue, AU - Zhuang,Xiaodong, AU - Huang,Zena, AU - Zou,Jing, AU - Yang,Daya, AU - Hu,Xun, AU - Du,Zhimin, AU - Wang,Lichun, AU - Liao,Xinxue, Y1 - 2017/10/02/ PY - 2017/05/07/received PY - 2017/09/10/revised PY - 2017/09/28/accepted PY - 2017/10/7/pubmed PY - 2018/3/27/medline PY - 2017/10/7/entrez KW - Diabetic complications KW - Inflammation KW - Klotho KW - Oxidative stress SP - 238 EP - 251 JF - Biochimica et biophysica acta. Molecular basis of disease JO - Biochim Biophys Acta Mol Basis Dis VL - 1864 IS - 1 N2 - Cardiac inflammation and oxidative stress play a key role in the pathogenesis of diabetic cardiomyopathy (DCM). The anti-aging protein Klotho has been found to protect cells from inflammation and oxidative stress. The current study aimed to explore the cardioprotective effects of Klotho on DCM and the underlying mechanisms. H9c2 cells and neonatal cardiomyocytes were incubated with 33mM glucose in the presence or absence of Klotho. Klotho pretreatment effectively inhibited high glucose-induced inflammation, ROS generation, apoptosis, mitochondrial dysfunction, fibrosis and hypertrophy in both H9c2 cells and neonatal cardiomyocytes. In STZ-induced type 1 diabetic mice, intraperitoneal injection of Klotho at 0.01mg/kg per 48h for 3months 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 erythroid 2-related factor 2 (Nrf2) expression and inactivating nuclear factor κB (NF-κB) activation both in vitro and in vivo. Thus, this work demonstrated for the first time that the anti-aging protein Klotho may be a potential therapeutic agent to treat 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. SN - 0925-4439 UR - https://www.unboundmedicine.com/medline/citation/28982613/Klotho_protects_the_heart_from_hyperglycemia_induced_injury_by_inactivating_ROS_and_NF_κB_mediated_inflammation_both_in_vitro_and_in_vivo_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0925-4439(17)30355-1 DB - PRIME DP - Unbound Medicine ER -