Role of Kallistatin Treatment in Aging and Cancer by Modulating miR-34a and miR-21 Expression.

Julie Chao,Pengfei Li,Lee Chao,Youming Guo

doi:10.1155/2017/5025610

Julie Chao, Pengfei Li + Show 2 more

Open Access

https://doi.org/10.1155/2017/5025610

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Abstract

Kallistatin is an endogenous protein that regulates differential signaling pathways and a wide spectrum of biological activities via its two structural elements: an active site and a heparin-binding domain. Kallistatin via its heparin-binding site inhibits vascular inflammation and oxidative stress by antagonizing TNF-α-induced NADPH oxidase activity, NF-κB activation, and inflammatory gene expression in endothelial cells. Moreover, kallistatin via its active site inhibits microRNA-34a (miR-34a) synthesis and stimulates eNOS and SIRT1 expression in endothelial progenitor cells, whereas its heparin-binding site is crucial for blocking TNF-α-induced miR-21 expression and oxidative stress, thus reducing cellular senescence. By downregulating miR-34a and miR-21 expression, kallistatin treatment attenuates oxidative damage and aortic senescence in streptozotocin-induced diabetic mice and extends Caenorhabditis elegans lifespan under stress conditions. Likewise, kallistatin through the heparin-binding site inhibits TGF-β-induced miR-21 synthesis and oxidative stress in endothelial cells, resulting in inhibition of endothelial-mesenchymal transition, a process contributing to fibrosis and cancer. Furthermore, kallistatin's active site is essential for stimulating miR-34a and p53 expression and inhibiting the miR-21-Akt-Bcl-2 signaling pathway, thus inducing apoptosis in breast cancer cells. These findings reveal novel mechanisms of kallistatin in protection against senescence, aging, and cancer development by modulating miR-34a and miR-21 levels and inhibiting oxidative stress.

Highlights

Aging, characterized by the deterioration of human physiological functions, is the dominant risk factor for the development of cardiovascular disease and cancer [1]
Depletion of endogenous kallistatin by neutralizing antibody injection further increases oxidative stress, inflammation, and fibrosis and augments cardiovascular and renal damage in salt-induced hypertensive rats [47]. These findings indicate that kallistatin has a protective role in cardiovascular and renal dysfunction by inhibition of oxidative stress and inflammation
Kallistatin inhibits endothelial-tomesenchymal transition (EndMT) through suppressing the Transforming growth factor- (TGF-)β-induced miR-21-Akt-NFκB signaling pathway and stimulating antioxidant protein expression (Figure 2). These findings indicate that kallistatin attenuates fibrosis and cancer by suppressing TGF-βinduced EndMT

Summary

Introduction

Aging, characterized by the deterioration of human physiological functions, is the dominant risk factor for the development of cardiovascular disease and cancer [1]. Overexpression of miR-34a induces premature senescence of young mesangial cells via downregulation of SOD2, leading to an increase in ROS generation, while antisense miR-34a inhibits senescence of old mesangial cells via upregulation of SOD2 and a decrease in ROS [19] These findings indicate that miR-21 and miR-34a are pivotal players in aging and tumor progression. Kallistatin reduces TNF-α-induced endothelial senescence and delays stress-induced aging by inhibiting miR-34a, miR-21, and oxidative stress and upregulating the expression of the antioxidant enzymes eNOS, SIRT1, catalase, and SOD3 in cultured EPCs, streptozotocin- (STZ-) induced diabetic mice, and Caenorhabditis elegans (C. elegans). This review focuses on the protective role of kallistatin in cellular senescence, aging, and tumor progression by inhibiting oxidative stress and regulating miR-34a and miR-21 levels

Kallistatin Inhibits Oxidative Stress and Inflammation

Conclusion