Abstract 13655: DUSP-1 May Be a Key Regulator of NK Cell Function in Obesity Potentially Accelerating Cardiovascular Disease in African American Women

Abstract

Background: Obesity disproportionately affects African American (AA) women and contributes to disparate cardiovascular disease (CVD) outcomes. Natural killer cells have been shown to be functionally impaired by obesity. However, underlying mechanisms regulating NK cell function in obesity are largely unknown. Therefore, we sought to elucidate potential signaling pathways involved in obesity-related NK cell function loss in AA women. Methods: All experiments were performed with freshly isolated naïve NK cells. NK cells were isolated from AA women (n=29; 15 BMI<25, 14 BMI>30). NK cell function was measured by flow cytometry by determining the ability of NK cells to degranulate towards K562 cells. NK cell gene expression profile was determined by RNA sequencing to identify important signaling pathways, which were verified using chemical pathway inhibitors. Publicly available datasets were analyzed to determine the importance of identified target genes. Results: NK cells isolated from AA women with obesity displayed diminished capacity to induce K562 cell death as determined by decreased degranulation (decreased surface CD107a expression and decreased intracellular IFNγ and TNFα expression). RNA sequencing analysis of NK cells isolated from lean vs AA women with obesity revealed 1645 significantly regulated genes with DUSP-1 being in the top 50 and displaying a 2.8-fold upregulation in AA women with obesity (p=0.0009). Furthermore, DUSP-1 gene expression was significantly correlated with BMI (R 2 =0.72, p=0.02). In vitro experiments revealed a DUSP-1 inhibitor to enhance NK cell function. Additionally, analysis of publicly available RNA sequencing dataset (GSE20129) in women revealed an increase of DUSP-1 mRNA expression in Black and Latinx women with CVD when compared to women without CVD group; this difference was not observed in White women. Conclusion: Our data demonstrate that NK cells are functionally impaired in NK cells isolated from AA women with obesity. We identified DUSP-1 as a crucial regulator of the observed NK cell dysfunction in obesity, which may be of particular importance in CVD development and progression in AA women, a population disproportionally affected by obesity and CVD.