TY - JOUR
T1 - SP-A2 contributes to miRNA-mediated sex differences in response to oxidative stress
T2 - Pro-inflammatory, anti-apoptotic, and anti-oxidant pathways are involved
AU - Noutsios, George T.
AU - Thorenoor, Nithyananda
AU - Zhang, Xuesheng
AU - Phelps, David S.
AU - Umstead, Todd M.
AU - Durrani, Faryal
AU - Floros, Joanna
N1 - Funding Information:
This work was supported by NIHR01HL34788 and CHILD fund, Department of Pediatrics, College of Medicine, at Pennsylvania State University.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/4
Y1 - 2017/12/4
N2 - Background: Human innate host defense molecules, surfactant protein A1 (SP-A1), and SP-A2 differentially affect the function and proteome of the alveolar macrophage (AM). We hypothesized that SP-A genes differentially regulate the AM miRNome. Methods: Humanized transgenic mice expressing SP-A1 and SP-A2 were subjected to O3-induced oxidative stress (OxS) or filtered air (FA), AMs were isolated, and miRNA levels were measured. Results: In SP-A2 males, we found significant changes in miRNome in terms of sex and sex-OxS effects, with 11 miRNAs differentially expressed under OxS. Their mRNA targets included BCL2, CAT, FOXO1, IL6, NF-kB, SOD2, and STAT3. We followed the expression of these transcripts as well as key cytokines, and we found that (a) the STAT3 mRNA significantly increased at 4 h post OxS and returned to baseline at 18 h post OxS. (b) The anti-oxidant protein SOD2 level significantly increased, but the CAT level did not change after 4 h post OxS compared to control. (c) The anti-apoptotic BCL2 mRNA increased significantly (18 h post OxS), but the levels of the other transcripts were decreased. The presence of the SP-A2 gene had a protective role in apoptosis of AMs under OxS compared to mice lacking SP-A (knockout, KO). (d) Pro-inflammatory cytokine IL-6 protein levels were significantly increased in SP-A2 mice compared to KO (4 and 18 h post OxS), which signifies the role of SP-A2 in pro-inflammatory protein expression. (e) SOD2 and CAT mRNAs changed significantly in OxS indicating a plausible role of SP-A2 in the homeostasis of reactive oxygen species. (f) Gonadectomy of transgenic mice showed that sex hormones contribute to significant changes of the miRNome expression. Conclusions: We conclude that SP-A2 influences the miRNA-mediated sex-specific differences in response to OxS. In males, these differences pertain to inflammatory, anti-apoptotic, and anti-oxidant pathways.
AB - Background: Human innate host defense molecules, surfactant protein A1 (SP-A1), and SP-A2 differentially affect the function and proteome of the alveolar macrophage (AM). We hypothesized that SP-A genes differentially regulate the AM miRNome. Methods: Humanized transgenic mice expressing SP-A1 and SP-A2 were subjected to O3-induced oxidative stress (OxS) or filtered air (FA), AMs were isolated, and miRNA levels were measured. Results: In SP-A2 males, we found significant changes in miRNome in terms of sex and sex-OxS effects, with 11 miRNAs differentially expressed under OxS. Their mRNA targets included BCL2, CAT, FOXO1, IL6, NF-kB, SOD2, and STAT3. We followed the expression of these transcripts as well as key cytokines, and we found that (a) the STAT3 mRNA significantly increased at 4 h post OxS and returned to baseline at 18 h post OxS. (b) The anti-oxidant protein SOD2 level significantly increased, but the CAT level did not change after 4 h post OxS compared to control. (c) The anti-apoptotic BCL2 mRNA increased significantly (18 h post OxS), but the levels of the other transcripts were decreased. The presence of the SP-A2 gene had a protective role in apoptosis of AMs under OxS compared to mice lacking SP-A (knockout, KO). (d) Pro-inflammatory cytokine IL-6 protein levels were significantly increased in SP-A2 mice compared to KO (4 and 18 h post OxS), which signifies the role of SP-A2 in pro-inflammatory protein expression. (e) SOD2 and CAT mRNAs changed significantly in OxS indicating a plausible role of SP-A2 in the homeostasis of reactive oxygen species. (f) Gonadectomy of transgenic mice showed that sex hormones contribute to significant changes of the miRNome expression. Conclusions: We conclude that SP-A2 influences the miRNA-mediated sex-specific differences in response to OxS. In males, these differences pertain to inflammatory, anti-apoptotic, and anti-oxidant pathways.
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U2 - 10.1186/s13293-017-0158-2
DO - 10.1186/s13293-017-0158-2
M3 - Article
C2 - 29202868
AN - SCOPUS:85037111818
SN - 2042-6410
VL - 8
JO - Biology of Sex Differences
JF - Biology of Sex Differences
IS - 1
M1 - 37
ER -