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<0.05 vs control 196pg/mL); an effect blocked by NAC. TOR, DAL and ANA increased superoxide (2-fold) and H2O2 (1.5-fold) production, and STAT3 phosphorylation (p<0.05). TOR increased Nox1, 4 and 5 (2-fold); DAL increased Nox4 (2-fold) and, ANA increased Nox1 and 4 (3-fold). In TOR treated cells, Aldo production was inhibited by GKT (62%), ML171 (62%), Rot (45%), and S3I-201 (STAT3 inhibitor, 66%). DAL-induced Aldo production was blocked by ML171(62%) and S3I-201 (74%). In ANA treated cells, Aldo production was inhibited by GKT (94%), ML171 (83%), and Rot (66%). We also assessed effects of CETP inhibitors on chemerin production, a novel adipokine associated with hypertension. TOR, but not ANA or DAL stimulated chemerin production (331pg/mL vs control 154pg/mL p<0.05); an effect blocked by GKT (95%) and S3I-201 (100%). In mouse adipocytes, TOR, DAL, and ANA induced Aldo (453pg/mL, 375pg/mL, and 445pg/mL vs cont 253pg/mL, p<0.05) and ROS production (1.7-fold, p<0.05). In conclusion, CETP inbitors induced aldosterone production in human and mouse adipocytes through redox-related mechanisms involving STAT3, Noxs and mitochondria. These novel findings have important clinical significance and may explain, in part, the hyperaldosteronism and hypertension reported in CETP clinical trials.
Author Disclosures: F.J. Rios: None. K.B. Neves: None. A. Nguyen Dinh Cat: None. S. Even: None. R. Palacios: None. C. Jenkins: None. A. Carswell: None. A.C. Montezano: None. R.M. Touyz: None.
- © 2014 by American Heart Association, Inc.