Triacsin C Suppresses Non‐Esterified Fatty Acids (NEFA) and Increases Nitric Oxide (NO) Synthesis

Abstract

Endothelial dysfunction is characterized by decreased vascular NO availability. Elevated NEFA decreases eNOS activity. In cultured cells, we found that fatty acyl CoA synthase (FACS) inhibitor Triacsin C (TC) interrupted eNOS palmitoylation, increasing eNOS activity but not changing vascular‐active eicosanoids. Hypothesis: TC mitigates endothelial dysfunction by increasing NO and decreasing NEFA. In this study, intravascular NO synthesis was measured by electrochemistry in the ischemic hind limb with heparinized rat model in a time course design. The post‐ischemic NO was significantly elevated in TC (100 μg/kg)‐treated animals than controls. NOS inhibitor treatments in this model implicate a role of eNOS, but not iNOS. Acute hyperlipidemia was induced by a bolus dose of Intralipid®(1 ml) to increase NEFA. Pre‐treatment with TC had no effect on total plasma lipids or triglycerides, either before or after Intralipid®. TC reduced baseline plasma NEFA from 240 ± 26.8 to 147 ± 14.3 μg/ml (p=0.038). Fifteen minutes after Intralipid®, NEFA rose to 1461 ± 130 μg/ml (control), which was blunted by TC to 393 ± 2.55 μg/ml (p=0.0079). By 85 min., the difference had subsided (194 ± 10.2 control vs. 281 ± 74.8 μg/ml TC; p=0.74). The TC effect was not uniform across all fatty acid species measured. These data show that TC increases post‐ischemic eNOS activity and blunted plasma NEFA induced by acute hyperlipidemia.