Abstract 356: Torcetrapib and Dalcetrapib, CETP inhibitors, Induce Adipocyte-derived Aldosterone and Reactive Oxygen Species Formation

Abstract

Hyperaldosteronism and hypertension were major side effects observed in clinical trials with Torcetrapib (TORC), a CETP inhibitor that increases HDL. Reasons for this are unclear. Given that CETP inhibitors accumulate in adipose tissue and that adipocytes are a source of aldosterone, we questioned whether CETP inhibitors, TORC and Dalcetrapib (DALC), influence adipocyte aldosterone production. Putative mechanisms underlying this were also explored. Human adipocytes, expressing CETP were studied and compared to mouse adipocytes, which lack CETP gene. Human SW872 and 3T3-L1 adypocites were treated with TORC and DALC (1-30 μM). Reactive Oxygen Species (ROS) production was evaluated by lucigenin-enhanced chemiluminescence. Aldosterone levels were evaluated by ELISA. Gene expression for Mineralocoricoid Receptor (MR), PPARγ, aldosterone synthase (CYP11B2) and glucorticoid synthase (CYP11B1) were evaluated by real time PCR. In human adipocytes, TORC and DALC induced 2- and 1.5-fold increase respectively in ROS production after 5 min (p<0.05). Aldosterone production was observed after 5h stimulation for both drugs (TORC: 72.9 pg/mL; DALC: 78 pg/mL vs cont 49.7 pg/mL, p<0.05). DALC increased mRNA expression of CYP11B1 (40%), CYP11B2 (40%), GR (80%), MR (80%) and PPARγ (90%) (p<0.05). TORC increased the mRNA expression for CYP11B2 (37%) and PPARγ (41%) (p<0.05) and did not change the mRNA for CYP11B1 or MR. In mouse adipocytes, TORC and DALC induced aldosterone production (120 pg/mL and 117 pg/mL vs cont 79 pg/mL, p<0.05) but only DALC induced ROS production, 1.6-fold increase (p<0.05 vs cont). Both drugs induced aldosterone production in adipocytes and exerted different effects regarding adypocyte gene expression. These effects may not be related to CETP inhibition, since they were also observed in mouse cells. Our findings indicate that CETP inhibitors influence adipocyte function and stimulate adipocyte-derived aldosterone production. We also show that off-target activities of TORC and DALC are not necessarily due to CETP inhibition and might be dependent on ROS production. These novel findings have important clinical significance and may explain, in part, the aldosteronism/hypertension reported in CETP clinical trials.