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Free Radic Biol Med. 2013 Dec;65:1060-8. doi: 10.1016/j.freeradbiomed.2013.08.183. Epub 2013 Sep 3.

Angiotensin-(1-7) prevents radiation-induced inflammation in rat primary astrocytes through regulation of MAP kinase signaling.

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  • 1Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; Brain Tumor Center of Excellence, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA. Electronic address: elmoore2@wakehealth.edu.

Abstract

About 500,000 new cancer patients will develop brain metastases in 2013. The primary treatment modality for these patients is partial or whole brain irradiation which leads to a progressive, irreversible cognitive impairment. Although the exact mechanisms behind this radiation-induced brain injury are unknown, neuroinflammation in glial populations is hypothesized to play a role. Blockers of the renin-angiotensin system (RAS) prevent radiation-induced cognitive impairment and modulate radiation-induced neuroinflammation. Recent studies suggest that RAS blockers may reduce inflammation by increasing endogenous concentrations of the anti-inflammatory heptapeptide angiotensin-(1-7) [Ang-(1-7)]. Ang-(1-7) binds to the AT(1-7) receptor and inhibits MAP kinase activity to prevent inflammation. This study describes the inflammatory response to radiation in astrocytes characterized by radiation-induced increases in (i) IL-1β and IL-6 gene expression; (ii) COX-2 and GFAP immunoreactivity; (iii) activation of AP-1 and NF-κB transcription factors; and (iv) PKCα, MEK, and ERK (MAP kinase) activation. Treatment with U-0126, a MEK inhibitor, demonstrates that this radiation-induced inflammation in astrocytes is mediated through the MAP kinase pathway. Ang-(1-7) inhibits radiation-induced inflammation, increases in PKCα, and MAP kinase pathway activation (phosphorylation of MEK and ERK). Additionally Ang-(1-7) treatment leads to an increase in dual specificity phosphatase 1 (DUSP1). Furthermore, treatment with sodium vanadate (Na3VO4), a phosphatase inhibitor, blocks Ang-(1-7) inhibition of radiation-induced inflammation and MAP kinase activation, suggesting that Ang-(1-7) alters phosphatase activity to inhibit radiation-induced inflammation. These data suggest that RAS blockers inhibit radiation-induced inflammation and prevent radiation-induced cognitive impairment not only by reducing Ang II but also by increasing Ang-(1-7) levels.

© 2013 Published by Elsevier Inc.

KEYWORDS:

ACEI; ARB; Ang; Angiotensin; Angiotensin converting enzyme inhibitor; Angiotensin receptor blocker; Angiotensin-(1–7); COX-2; Cyclooxygenase-2; DUSP1; Dual specificity phosphatase 1; EMSA; ERK; Electromobility-shift assay; Extracellular signal-regulated kinase; Fractionated whole brain irradiation; GFAP; Glial fibrillary acidic protein; IL; Interleukin; MAP kinase signaling; MEK; Mitogen-activated protein erk kinase; RAS; Radiation-induced Inflammation; Rat primary astrocytes; Renin-angiotensin system; TNF-α; Tumor necrosis factor-α; fWBI

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