Thompson, Lauren; Ramous, Caroline; Ly, Kellsey; Luu, Kiana; Margetts, Alex; Warren, Tahno; Tippetts, Trevor; Choi, Ran Hee; Symons, JD (University of Utah)
Faculty Advisor: Symons, J. David (University of Utah, Nutrition and Integrative Physiology)
Type II diabetes mellitus (T2DM) is an epidemic worldwide. Cardiovascular complications (e.g. endothelial dysfunction and hypertension) are associated with T2DM. T2DM affects the quality of life for the patient and their caregivers, and the costs for treating cardiovascular complications are unsustainable. An urgent need exists to elucidate new therapeutic targets for intervention. Our laboratory is interested in defining the contribution from the sphingolipid ceramide. We reported earlier that arterial dysfunction and hypertension that otherwise develop in mice that consume an obesogenic diet is attenuated by pharmacological inhibition of ceramide using myriocin and by germline haploinsufficiency for dihydroceramide desaturase (DES1), an enzyme required for ceramide biosynthesis. However, each study had limitations. Myriocin improved systemic glucose homeostasis, and DES1 inhibition elevated dihydroceramides, both of which could impact arterial function. In the present study, we used a novel murine model to inhibit the rate-limiting enzyme responsible for ceramide biosynthesis (serine palmitoyl transferase light chain 2; Sptlc2) specifically in endothelial cells (ECs). We hypothesized that EC specific inhibition of ceramide biosynthesis would preserve arterial function in obese mice. Six-week-old male mice with intact Sptlc2 (wild-type; WT) and EC specific deletion of Sptlc2 (iecSptlc2KO mice) consumed either standard (CON) or high fat diet (HFD) for 14 weeks. qPCR results indicated Sptlc2 was knocked down > 80% in ECs but not media and adventitia from iecSptlc2KO vs. WT mice. In general, results were similar between WT and iecSptlc2KO mice concerning glucose, insulin, and pyruvate tolerance tests (indicating intact glucose homeostasis) and lean mass, fat mass, and fluid mass (indicating body composition was unaltered). Of note, intraluminal flow-mediated vasodilation was greater in femoral arteries from iecSptlc2KO vs. WT mice that consumed high-fat chow. Preventing ceramide biosynthesis specifically in ECs from mice that consume an obesogenic diet might be vasculoprotective.