Klotho inhibits IGF1R/PI3K/AKT signalling pathway and protects the heart from oxidative stress during ischemia/reperfusion injury-Reference-Cited by-同舟云学术

Klotho inhibits IGF1R/PI3K/AKT signalling pathway and protects the heart from oxidative stress during ischemia/reperfusion injury

Published:2023-09-01 Issue: Volume: Page:
ISSN:
Container-title:
language:
Short-container-title:

Author:

Olejnik Agnieszka¹,Radajewska Anna¹,Krzywonos-Zawadzka Anna¹,Bil-Lula Iwona¹

Affiliation:

1. Wroclaw Medical University

Abstract

Abstract Ischemia/reperfusion injury (IRI) of the heart involves the activation of oxidative and proapoptotic pathways. Simultaneously Klotho protein presents anti-aging, antiapoptotic and antioxidative properties. Therefore, this study aimed to evaluate the effect of Klotho protein on oxidative stress in hearts subjected to IRI. Isolated rat hearts perfused with the Langendorff method were subjected to ischemia, followed by reperfusion, in the presence or absence of recombinant rat Klotho protein. The factors involved in the activation of insulin-like growth factor receptor (IGF1R)/phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT) signalling pathway were evaluated. IRI caused activation of the IGF1R (p = 0.0122)/PI3K (p = 0.0022) signalling, as compared to the aerobic control group. Infusion supply of Klotho protein during IRI significantly reduced the level of phospho-IGF1R (p = 0.0436), PI3K (p = 0.0218) and phospho-AKT (p = 0.0020). Transcriptional activity of forkhead box protein O3 (FOXO3) was reduced (p = 0.0207) in hearts subjected to IRI, compared to aerobic control. Administration of Klotho decreased phosphorylation of FOXO3 (p = 0.0355), and enhanced activity of glutathione peroxidase (p = 0.0452) and superoxide dismutase (p = 0.0060) in IRI + Klotho group. The levels of reactive oxygen/nitrogen species (ROS/RNS) (p = 0.0480) and hydrogen peroxide (H2O2) (p = 0.0460), and heart injury (p = 0.0005) were significantly increased in hearts from the IRI group in comparison to the aerobic group. Klotho reduced NADPH oxidase 2 (NOX2) (p = 0.0390), ROS/RNS (p = 0.0435) and H2O2 (p = 0.0392) levels, and heart damage (p = 0.0286) in the hearts subjected to IRI. In conclusion, Klotho contributed to the protection of the heart against IRI and oxidative stress via inhibition of the IGF1R/PI3K/AKT pathway, thus can be recognized as a novel cardiopreventive/cardioprotective agent.

Publisher

Research Square Platform LLC

Reference81 articles.

1. Kalogeris, T., Baines, C. P., Krenz, M. & Korthuis, R. J. Chapter Six - Cell Biology of Ischemia/Reperfusion Injury. Int. Rev. Cell Mol. Biol. (ed. Jeon, K. W.) vol. 298 229–317 (Academic Press, 2012).

2. Oxidative stress and heart failure;Tsutsui H;Am. J. Physiol.-Heart Circ. Physiol.,2011

3. O-Uchi, J., Jhun, B. S., Mishra, J. & Sheu, S.-S. 7 - Organellar Ion Channels and Transporters. Cardiac Electrophysiology: From Cell to Bedside (Seventh Edition) (eds. Zipes, D. P., Jalife, J. & Stevenson, W. G.) 66–79 (Elsevier, 2018).

4. The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology;Bedard K;Physiol. Rev.,2007

5. Wang, Y., Zhou, Y. & Graves, D. T. FOXO Transcription Factors: Their Clinical Significance and Regulation. BioMed Res. Int. 2014, e925350 (2014).