Opposing Effects of Oxygen Regulation on Kallistatin Expression: Kallistatin as a Novel Mediator of Oxygen-Induced HIF-1-eNOS-NO Pathway.

Julie Chao,Youming Guo,Pengfei Li,Lee Chao

doi:10.1155/2017/5262958

Abstract

Oxidative stress has both detrimental and beneficial effects. Kallistatin, a key component of circulation, protects against vascular and organ injury. Serum kallistatin levels are reduced in patients and animal models with hypertension, diabetes, obesity, and cancer. Reduction of kallistatin levels is inversely associated with elevated thiobarbituric acid-reactive substance. Kallistatin therapy attenuates oxidative stress and increases endothelial nitric oxide synthase (eNOS) and NO levels in animal models. However, kallistatin administration increases reactive oxygen species formation in immune cells and bacterial killing activity in septic mice. High oxygen inhibits kallistatin expression via activating the JNK-FOXO1 pathway in endothelial cells. Conversely, mild oxygen/hyperoxia stimulates kallistatin, eNOS, and hypoxia-inducible factor-1 (HIF-1) expression in endothelial cells and in the kidney of normal mice. Likewise, kallistatin stimulates eNOS and HIF-1, and kallistatin antisense RNA abolishes oxygen-induced eNOS and HIF-1 expression, indicating a role of kallistatin in mediating mild oxygen's stimulation on antioxidant genes. Protein kinase C (PKC) activation mediates HIF-1-induced eNOS synthesis in response to hyperoxia/exercise; thus, mild oxygen through PKC activation stimulates kallistatin-mediated HIF-1 and eNOS synthesis. In summary, oxidative stress induces down- or upregulation of kallistatin expression, depending on oxygen concentration, and kallistatin plays a novel role in mediating oxygen/exercise-induced HIF-1-eNOS-NO pathway.

Highlights

Kallistatin was first identified in human plasma as a tissue kallikrein-binding protein (KBP) and characterized as a serine proteinase inhibitor [1,2,3]
Kallistatin via its heparin-binding site interacts with cell surface heparan sulfate proteoglycans and thereby antagonizes the signaling pathways mediated by vascular endothelial growth factor, tumor necrosis factor-α, transforming growth factor-β, and Wnt [8,9,10,11]
Mild hyperoxia via protein kinase C (PKC) activation increases hypoxia-inducible factor-1 (HIF-1) synthesis, and eccentric exercise induces HIF-1-mediated-endothelial nitric oxide synthase (eNOS) expression [44,45,46,47,48]. These findings indicate that kallistatin is a novel mediator of mild oxygen-induced HIF-1 and eNOS synthesis, and mild oxygen through Protein kinase C (PKC) activation stimulates kallistatinmediated HIF-1-eNOS pathway

Summary

Introduction

Kallistatin was first identified in human plasma as a tissue kallikrein-binding protein (KBP) and characterized as a serine proteinase inhibitor (serpin) [1,2,3]. Damage, and cancer development by reducing oxidative stress, inflammation, angiogenesis, apoptosis, fibrosis, tumor growth, and metastasis in rodents [8, 20,21,22,23,24,25] These findings indicate that kallistatin therapy has beneficial effects in various disease states. Reduced kallistatin levels are inversely associated with elevated serum thiobarbituric acid reactive substances (TBARs, an indicator of lipid peroxidation) in hypertensive DSS rats and in STZ-induced diabetic rats (Figures 1(a), 1(b), 1(c), and 1(d)). Kallistatin levels are reduced in diseased states and, negatively associated with oxidative stress

Kallistatin Treatment Reduces Oxidative Stress and Organ Damage

High Oxygen Downregulates Kallistatin Expression

Kallistatin Mediates Mild Oxygen-Induced HIF-1 and eNOS Synthesis

Findings

Conclusion