Cd4+ T cell-specific proteomic pathways identified in progression of hypertension across postmenopausal transition

Joshua A. Uhlorn, Nathaniel A. Husband, Melissa J. Romero-Aleshire, Caitlin Moffett, Merry L. Lindsey, Paul R. Langlais, Heddwen L. Brooks

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article numbere018038
Pages (from-to)1-54
Number of pages54
JournalJournal of the American Heart Association
Volume10
Issue number2
DOIs
StatePublished - 2021

Keywords

  • 4-vinylcyclohexene diepoxide
  • Ang II
  • Menopause
  • Phosphoproteomics
  • Proteomics
  • T cells

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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