title: Off-Target Vascular Effects of Cholesteryl Ester Transfer Protein Inhibitors Involve Redox-Sensitive and Signal Transducer and Activator of Transcription 3-Dependent Pathways.
abstract: Elevated blood pressure was an unexpected outcome in some cholesteryl ester transfer protein (CETP) inhibitor trials, possibly due to vascular effects of these drugs. We investigated whether CETP inhibitors (torcetrapib, dalcetrapib, anacetrapib) influence vascular function and explored the putative underlying molecular mechanisms. Resistance arteries and vascular smooth muscle cells (VSMC) from rats, which lack the CETP gene, were studied. CETP inhibitors increased phenylephrine-stimulated vascular contraction (logEC50 (:) 6.6 ± 0.1; 6.4 ± 0.06, and 6.2 ± 0.09 for torcetrapib, dalcetrapib, and anacetrapib, respectively, versus control 5.9 ± 0.05). Only torcetrapib reduced endothelium-dependent vasorelaxation. The CETP inhibitor effects were ameliorated by N-acetylcysteine (NAC), a reactive oxygen species (ROS) scavenger, and by S3I-201 [2-hydroxy-4-[[2-(4-methylphenyl)sulfonyloxyacetyl]amino]benzoic acid], a signal transducer and activator of transcription 3 (STAT3) inhibitor. CETP inhibitors increased the phosphorylation (2- to 3-fold) of vascular myosin light chain (MLC) and myosin phosphatase target subunit 1 (MYPT1) (procontractile proteins) and stimulated ROS production. CETP inhibitors increased the phosphorylation of STAT3 (by 3- to 4-fold), a transcription factor important in cell activation. Activation of MLC was reduced by NAC, GKT137831 [2-(2-chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6-dione] (Nox1/4 inhibitor), and S3I-201. The phosphorylation of STAT3 was unaffected by NAC and GKT137831. CETP inhibitors did not influence activation of mitogen-activated proteins kinases (MAPK) or c-Src. Our data demonstrate that CETP inhibitors influence vascular function and contraction through redox-sensitive, STAT3-dependent, and MAPK-independent processes. These phenomena do not involve CETP because the CETP gene is absent in rodents. Findings from our study indicate that CETP inhibitors have vasoactive properties, which may contribute to the adverse cardiovascular effects of these drugs such as hypertension.
authors.affiliation: Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, United Kingdom (F.J.R., R.A.L., K.B.N., L.L.C., A.C.M., R.M.T.); Ribeirao Preto Medical School (R.A.L.) and Faculty of Pharmaceutical Sciences of Ribeirao Preto (K.B.N.), University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Rios
authors.affiliation: Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, United Kingdom (F.J.R., R.A.L., K.B.N., L.L.C., A.C.M., R.M.T.); Ribeirao Preto Medical School (R.A.L.) and Faculty of Pharmaceutical Sciences of Ribeirao Preto (K.B.N.), University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Rheure A
authors.initials: RA
authors.lastname: Lopes
authors.affiliation: Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, United Kingdom (F.J.R., R.A.L., K.B.N., L.L.C., A.C.M., R.M.T.); Ribeirao Preto Medical School (R.A.L.) and Faculty of Pharmaceutical Sciences of Ribeirao Preto (K.B.N.), University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Karla B
authors.initials: KB
authors.lastname: Neves
authors.affiliation: Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, United Kingdom (F.J.R., R.A.L., K.B.N., L.L.C., A.C.M., R.M.T.); Ribeirao Preto Medical School (R.A.L.) and Faculty of Pharmaceutical Sciences of Ribeirao Preto (K.B.N.), University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Livia L
authors.initials: LL
authors.lastname: Camargo
authors.affiliation: Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, United Kingdom (F.J.R., R.A.L., K.B.N., L.L.C., A.C.M., R.M.T.); Ribeirao Preto Medical School (R.A.L.) and Faculty of Pharmaceutical Sciences of Ribeirao Preto (K.B.N.), University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Augusto C
authors.initials: AC
authors.lastname: Montezano
authors.affiliation: Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, United Kingdom (F.J.R., R.A.L., K.B.N., L.L.C., A.C.M., R.M.T.); Ribeirao Preto Medical School (R.A.L.) and Faculty of Pharmaceutical Sciences of Ribeirao Preto (K.B.N.), University of Sao Paulo, Ribeirao Preto, Brazil Rhian.Touyz@glasgow.ac.uk.
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D016166:Free Radical Scavengers / Q000494:pharmacology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D019255:NADPH Oxidases / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D047069:Pyrazolones; D011725:Pyridines / Q000494:pharmacology; D011728:Pyridones; D051381:Rats; D011921:Rats, Inbred WKY; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D014655:Vascular Resistance / Q000187:drug effects / Q000235:genetics; D014661:Vasoconstriction / Q000187:drug effects / Q000235:genetics; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D053480:Cholesterol Ester Transfer Proteins; D016166:Free Radical Scavengers; D011720:Pyrazoles; D047069:Pyrazolones; D011725:Pyridines; D011728:Pyridones; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D014665:Vasodilator Agents; C576694:setanaxib; D019255:NADPH Oxidases; D020928:Mitogen-Activated Protein Kinases; C499850:Ppp1r12a protein, rat; D054645:Protein Phosphatase 1; D000111:Acetylcysteine