Cholesteryl ester-transfer protein inhibitors stimulate aldosterone biosynthesis in adipocytes through nox-dependent processes

Rios, F., Neves, K. B., Nguyen Dinh Cat, A., Even, S., Palacios, R. , Montezano, A. C. and Touyz, R. (2015) Cholesteryl ester-transfer protein inhibitors stimulate aldosterone biosynthesis in adipocytes through nox-dependent processes. Journal of Pharmacology and Experimental Therapeutics, 353(1), pp. 27-34. (doi:10.1124/jpet.114.221002) (PMID:25617244)

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Abstract

Hyperaldosteronism and hypertension were unexpected side effects observed in trials of torcetrapib, a cholesteryl ester-transfer protein (CETP) inhibitor that increases high-density lipoprotein. Given that CETP inhibitors are lipid soluble, accumulate in adipose tissue, and have binding sites for proteins involved in adipogenesis, and that adipocytes are a source of aldosterone, we questioned whether CETP inhibitors (torcetrapib, dalcetrapib, and anacetrapib) influence aldosterone production by adipocytes. Studies were performed using human adipocytes (SW872), which express CETP, and mouse adipocytes (3T3-L1), which lack the CETP gene. Torcetrapib, dalcetrapib, and anacetrapib increased expression of CYP11B2, CYP11B1, and steroidogenic acute regulatory protein, enzymes involved in mineralocorticoid and glucocorticoid generation. These effects were associated with increased reactive oxygen species formation. Torcetrapib, dalcetrapib, and anacetrapib upregulated signal transducer and activator of transcription 3 (STAT3) and peroxisome proliferation-activated receptor-γ, important in adipogenesis, but only torcetrapib stimulated production of chemerin, a proinflammatory adipokine. To determine mechanisms whereby CETP inhibitors mediate effects, cells were pretreated with inhibitors of Nox1/Nox4 [GKT137831; 2-(2-chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione], Nox1 (ML171 [2-acetylphenothiazine]), mitochondria (rotenone), and STAT3 (S3I-201 [2-hydroxy-4-(((4-methylphenyl)sulfonyloxy)acetyl)amino)-benzoic acid]). In torcetrapib-stimulated cells, Nox inhibitors, rotenone, and S3I-201 downregulated CYP11B2 and steroidogenic acute regulatory protein and reduced aldosterone. Dalcetrapib and anacetrapib effects on aldosterone were variably blocked by GKT137831, ML171, rotenone, and S3I-201. In adipocytes, torcetrapib, dalcetrapib, and anacetrapib inhibit enzymatic pathways responsible for aldosterone production through Nox1/Nox4- and mitochondrial-generated reactive oxygen species and STAT3. CETP inhibitors also influence adipokine production. These processes may be CETP independent. Our findings identify novel adipocyte-related mechanisms whereby CETP inhibitors increase aldosterone production. Such phenomena may contribute to hyperaldosteronism observed in CETP inhibitor clinical trials.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Montezano, Dr Augusto and Nguyen Dinh Cat, Dr Aurelie and Palacios, Mr Roberto and Touyz, Professor Rhian and Rios, Dr Francisco
Authors: Rios, F., Neves, K. B., Nguyen Dinh Cat, A., Even, S., Palacios, R., Montezano, A. C., and Touyz, R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Journal of Pharmacology and Experimental Therapeutics
Publisher:American Society for Pharmacology and Experimental Therapeutics
ISSN:0022-3565
ISSN (Online):1521-0103

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
607383Vascular Noxs as therapeutic targets and biomarkers in hypertensionRhian TouyzBritish Heart Foundation (BHF)IG/13/1/30087RI CARDIOVASCULAR & MEDICAL SCIENCES
607382Vascular Noxs as therapeutic targets and biomarkers in hypertensionRhian TouyzBritish Heart Foundation (BHF)RG/13/7/30099RI CARDIOVASCULAR & MEDICAL SCIENCES