Novel gene regulatory networks identified in response to nitro-conjugated linoleic acid in human endothelial cells

Abstract

Endothelial cell (EC) dysfunction is a crucial initiation event in the development of atherosclerosis and is associated with diabetes mellitus, hypertension, and heart failure. Both digestive and oxidative inflammatory conditions lead to the endogenous formation of nitrated derivatives of unsaturated fatty acids (FAs) upon generation of the proximal nitrating species nitrogen dioxide (·NO2) by nitric oxide (·NO) and nitrite-dependent reactions. Nitro-FAs (NO2-FAs) such as nitro-oleic acid (NO2-OA) and nitro-linoleic acid (NO2-LA) potently inhibit inflammation and oxidative stress, regulate cellular functions, and maintain cardiovascular homeostasis. Recently, conjugated linoleic acid (CLA) was identified as the preferential FA substrate of nitration in vivo. However, the functions of nitro-CLA (NO2-CLA) in ECs remain to be explored. In the present study, a distinct transcriptome regulated by NO2-CLA was revealed in primary human coronary artery endothelial cells (HCAECs) through RNA sequencing. Differential gene expression and pathway enrichment analysis identified numerous regulatory networks including those related to the modulation of inflammation, oxidative stress, cell cycle, and hypoxic responses by NO2-CLA, suggesting a diverse impact of NO2-CLA and other electrophilic nitrated FAs on cellular processes. These findings extend the understanding of the protective actions of NO2-CLA in cardiovascular diseases and provide new insight into the underlying mechanisms that mediate the pleiotropic cellular responses to NO2-CLA.