Interleukin-8 (IL-8) as a Potential Mediator of an Association between Trimethylamine N-Oxide (TMAO) and Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) among African Americans at Risk of Cardiovascular Disease

Alyssa M Baginski; Nicole Farmer; Yvonne Baumer; Gwenyth R Wallen; Tiffany M Powell-Wiley

doi:10.3390/metabo12121196

Interleukin-8 (IL-8) as a Potential Mediator of an Association between Trimethylamine N-Oxide (TMAO) and Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) among African Americans at Risk of Cardiovascular Disease

Metabolites. 2022 Nov 30;12(12):1196. doi: 10.3390/metabo12121196.

Authors

Alyssa M Baginski¹, Nicole Farmer¹, Yvonne Baumer², Gwenyth R Wallen¹, Tiffany M Powell-Wiley^{2

3}

Affiliations

¹ Translational, Biobehavioral, and Health Disparities Branch, National Institutes of Health Clinical Center, Bethesda, MD 20892, USA.
² Social Determinants of Obesity and Cardiovascular Risk Laboratory, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
³ Intramural Research Program, National Institute on Minority Health and Health Disparities, Bethesda, MD 20892, USA.

Abstract

Trimethylamine N-oxide (TMAO)-a microbial metabolite derived from the hepatic-gut axis-is linked to inflammation, hyperlipidemia, and cardiovascular disease (CVD). Proprotein convertase subtilisin/kexin type 9 (PCSK9), which is largely hepatically expressed, blocks low-density lipoprotein (LDL) receptor recycling, also leading to hyperlipidemia. The primary objective of this study was to investigate a previously hypothesized potential relationship between TMAO and PCSK9 in order to explore novel mechanisms linking TMAO and CVD risk. African American adults at risk of CVD living in the Washington DC area were recruited to participate in a cross-sectional community-based study (n = 60, 93% female, BMI = 33). Fasting levels of inflammatory cytokines (i.e., interleukin (IL)-1 beta, tumor necrosis factor-alpha, and interleukin-8), TMAO, and PCSK9 were measured using Luminex and ELISA, respectively. Univariate and multivariate linear regression analyses and structural equation mediation analyses were conducted using STATA. All models were adjusted for body mass index (BMI) and atherosclerotic CVD risk score (ASCVD). A significant association between TMAO and PCSK9 was identified (β = 0.31, p = 0.02). Both TMAO and PCSK9 were significantly associated with IL-8 (TMAO: β = 0.45, p = 0.00; PCSK9: β = 0.23, p = 0.05) in adjusted models. Mediation analysis indicated that 34.77% of the relationship between TMAO and PCSK9 was explained by IL-8. Our findings indicate a potential PCSK9-involved pathway for TMAO and CVD risk, with potential mediation by IL-8.

Keywords: PCSK9; TMAO; cardiovascular disease; inflammation.

Grants and funding

This research was funded by the 2020 William G. Coleman Award from the National Institute on Minority Health and Health Disparities. This research was also supported through the Intramural Research Program at the National Institutes of Health Clinical Center, the National Heart Lung and Blood Institute, and the National Institute on Minority Health and Health Disparities.