ETA receptor activation on vascular smooth muscle cells mediates inflammation via IL-6

In obesity, there is a shift to a pro-inflammatory immune cell profile in adipose tissue, producing adipocyte dysfunction that leads to dyslipidemia and insulin resistance. Endothelin-1 (ET-1) is a proinflammatory peptide produced by endothelial cells that is increased in obesity. Our lab recently demonstrated that blockade of ET-1 type A receptors (ET A ) attenuates the pro-inflammatory immune cell profile in adipose tissue of obese mice. This is not due to activation of ET A receptors on adipocytes because adipocyte-specific ET A knockout did not attenuate adipose tissue inflammation in obese mice. Given the abundance of ET A on vascular smooth muscle cells (VSMC), we hypothesize that ET-1 binds ET A on vascular smooth muscle cells leading to release of proinflammatory cytokines. To test this hypothesis, human vascular smooth muscle cells were treated with ET-1 and co-treated with either vehicle, BQ-123 (ET A antagonist), or BQ-788 (ET B antagonist) and mRNA and protein release of several cytokines were measured. Treatment with ET-1 led to a significant increase in interleukin-6 (IL-6) mRNA expression (77993 ± 9716 vs. 142133 ± 19181 copy count/50ng RNA) and protein release into the media (315±27 vs. 569±17 pg/mL). The increase in IL-6 production was attenuated by treatment with BQ-123 (331±7 pg/mL), but not BQ-788 (583±4 pg/mL). There was no difference in tumor necrosis factor alpha, transforming growth factor beta, or interferon gamma in cells treated with ET-1 compared to vehicle. These data suggest that elevated ET-1 may promote inflammation in obesity by increasing IL-6 production by vascular smooth muscle cells. 5R01DK124327-02 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.