Gender differences in circulating inflammatory, immune, & tissue growth markers associated with Fabry disease-related cardiomyopathy

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.