TY - JOUR
T1 - Cd4+ T cell-specific proteomic pathways identified in progression of hypertension across postmenopausal transition
AU - Uhlorn, Joshua A.
AU - Husband, Nathaniel A.
AU - Romero-Aleshire, Melissa J.
AU - Moffett, Caitlin
AU - Lindsey, Merry L.
AU - Langlais, Paul R.
AU - Brooks, Heddwen L.
N1 - Funding Information:
This work was funded by grants from the National Heart, Lung, and Blood Institute, RO1HL131834, T32HL007249 and National Institute of Diabetes and Digestive and Kidney Diseases RO1DK098493.
Publisher Copyright:
© 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.
PY - 2021
Y1 - 2021
N2 - BACKGROUND: Menopause is associated with an increase in the prevalence and severity of hypertension in women. Although premenopausal females are protected against T cell-dependent immune activation and development of angiotensin II (Ang II) hypertension, this protection is lost in postmenopausal females. Therefore, the current study hypothesized that specific CD4+ T cell pathways are regulated by sex hormones and Ang II to mediate progression from premenopausal protection to postmenopausal hypertension. METHODS AND RESULTS: Menopause was induced in C57BL/6 mice via repeated 4-vinylcyclohexene diepoxide injections, while premenopausal females received sesame oil vehicle. A subset of premenopausal mice and all menopausal mice were infused with Ang II for 14 days (Control, Ang II, Meno/Ang II). Proteomic and phosphoproteomic profiles of CD4+ T cells isolated from spleens were examined. Ang II markedly increased CD4+ T cell protein abundance and phosphorylation associated with DNA and histone methylation in both premenopausal and postmenopausal females. Compared with premenopausal T cells, Ang II infusion in menopausal mice increased T cell phosphorylation of MP2K2, an upstream regulator of ERK, and was associated with upregulated phosphorylation at ERK targeted sites. Additionally, Ang II infusion in menopausal mice decreased T cell phosphorylation of TLN1, a key regulator of IL-2Rα and FOXP3 expression. CONCLUSIONS: These findings identify novel, distinct T cell pathways that influence T cell-mediated inflammation during postmenopausal hypertension.
AB - BACKGROUND: Menopause is associated with an increase in the prevalence and severity of hypertension in women. Although premenopausal females are protected against T cell-dependent immune activation and development of angiotensin II (Ang II) hypertension, this protection is lost in postmenopausal females. Therefore, the current study hypothesized that specific CD4+ T cell pathways are regulated by sex hormones and Ang II to mediate progression from premenopausal protection to postmenopausal hypertension. METHODS AND RESULTS: Menopause was induced in C57BL/6 mice via repeated 4-vinylcyclohexene diepoxide injections, while premenopausal females received sesame oil vehicle. A subset of premenopausal mice and all menopausal mice were infused with Ang II for 14 days (Control, Ang II, Meno/Ang II). Proteomic and phosphoproteomic profiles of CD4+ T cells isolated from spleens were examined. Ang II markedly increased CD4+ T cell protein abundance and phosphorylation associated with DNA and histone methylation in both premenopausal and postmenopausal females. Compared with premenopausal T cells, Ang II infusion in menopausal mice increased T cell phosphorylation of MP2K2, an upstream regulator of ERK, and was associated with upregulated phosphorylation at ERK targeted sites. Additionally, Ang II infusion in menopausal mice decreased T cell phosphorylation of TLN1, a key regulator of IL-2Rα and FOXP3 expression. CONCLUSIONS: These findings identify novel, distinct T cell pathways that influence T cell-mediated inflammation during postmenopausal hypertension.
KW - 4-vinylcyclohexene diepoxide
KW - Ang II
KW - Menopause
KW - Phosphoproteomics
KW - Proteomics
KW - T cells
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U2 - 10.1161/JAHA.120.018038
DO - 10.1161/JAHA.120.018038
M3 - Article
C2 - 33410333
AN - SCOPUS:85099820954
SN - 2047-9980
VL - 10
SP - 1
EP - 54
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 2
M1 - e018038
ER -