Abstract 584: Myeloid Kruppel-like Factor 14 Mediates Sexual Dimorphism Of Abdominal Aortic Aneurysm Via Estrogen Receptor β

Abstract

Rationale: Abdominal aortic aneurysm (AAA) is an irreversible degenerative disease of the abdominal aorta. Monocytes/macrophages are important mediators of inflammation and proteolysis during AAA development. In both human and rodent models, AAA has strong sexual dimorphism with a 4-6-fold higher prevalence in males than females, largely attributed to the estrogen/estrogen receptor signaling pathway. Krüppel-Like Factor 14 (KLF14) mediates anti-inflammatory response during disease pathogenesis and shows sexual heterogeneity in human genetic studies. However, whether and how KLF14 regulates sexual dimorphism during AAA progression has largely been unknown. Objective: Herein, we generated a novel insight into the anti-inflammatory effect and sexual dimorphic regulation of KLF14 during AAA pathogenesis. Methods and Results: We induced AAA model in myeloid cell-specific Klf14 knockout mice in ApoE -deficient background ( Klf14 LysM ApoE -/- ) and their littermate control mice ( Klf14 fl/fl ApoE -/- ). Klf14 deficiency in macrophages completely abrogated the sexual dimorphism observed in control mice by showing higher AAA incidence with more macrophage infiltration and more severe elastin degradation in female mice. Mechanistically, KLF14 upregulates the transcription of estrogen receptors, especially ESR2 , in macrophages. Perhexiline, a KLF14 inducer, induces Esr2 expression dependent on Klf14 and exerts an anti-inflammatory effect partially dependent on Esr2 in macrophages. Furthermore, Klf14 or Esr2 deficiency in macrophages abolished the protective effect of exogenous estradiol (E 2 ) treatment in male control mice. Conclusions: These studies provide evidence that Klf14 deficiency within myeloid lineage cells accelerated AAA development in female mice, resulting in the loss of sexual dimorphism in AAA pathogenesis. KLF14 showed protective effects, likely via transcriptionally regulating ESR2 expression and suppressing inflammation.