Abstract 009: CETP inhibitors Torcetrapib, Dalcetrapib, and Anacetrapib induce adipocyte-derived Aldosterone production through Nox and STAT3 activation

Large clinical trials indicated that CETP inhibitors increase HDL levels, but had unexpected side effects, such as hyperaldosteronism and hypertension. Some CETP inhibitors appear to accumulate in adipocytes, which are a source of aldosterone (Aldo). As such, we questioned whether CETP inhibitors influence Aldo production in adipocytes and assessed the role of reactive oxygen species (ROS) and STAT3 in this process. Human adipocytes (SW872), expressing CETP, were studied and compared to mouse adipocytes (3T3-L1), lacking CETP. Cells were treated with torcetrapib (TOR), dalcetrapib (DAL), or anacetrapib (ANA). To evaluate the role of ROS, cells were pre-treated with N-acetylcystein (NAC-ROS scavenger), ML171 and GKT136901 (Nox1/4 inhibitor, respectively), and Rotenone (Rot, mitochondrial ROS inhibitor). ROS were measured by lucigenin and amplex red. Aldo production, measured by ELISA, was induced by TOR (668pg/mL), DAL (348pg/mL) and ANA (434pg/mL) (p