Abstract 18757: Adenylate Cyclase Type 9 (Adcy9) Regulates Vasomotor Tone in Mice
Single nucleotide polymorphisms located in the adenylate cyclase type 9 (ADCY9) gene determine cardiovascular outcomes of patients treated with dalcetrapib, a cholesteryl ester transfer protein inhibitor (Tardif et al, Circ Cardiovasc Genetics 2015). The roles of the different subtypes of adenylate cyclases responsible for vasodilatation (VD) are ill-defined. We aimed at evaluating the role of Adcy9 expression in the control of vascular tone by using isolated vessels from Adcy9-inactivated (Adcy9Gt) and wild-type (WT) mice. Vasomotor tone was studied by recording the isometric tension developed by aorta rings and the diameter of pressurized isolated femoral arteries from mice aged 8 to 13 weeks. We studied VD in response to adenylate cyclase activators, isoproterenol (Iso), a β-adrenergic receptor (β-AR) agonist and iloprost, a prostaglandin I2 receptor agonist, as well as endothelial-dependent vasodilatation (EDV) in response to acetylcholine (Ach). EDV and β-AR-induced VD in the aorta were similar in WT and Adcy9Gt mice. In femoral arteries, Adcy9 inactivation decreased Iso-induced VD (Emax, WT: 48.3+/-4.7%, n=7; Adcy9Gt: 24.1+/-4.7%, n=11; P<0.01). In contrast, Iloprost-induced VD was not modified by Adcy9 inactivation (Emax, WT: 35.1+/-6.6%, n=7; Adcy9Gt: 39.5+/-5.6%, n=8). Surprisingly, Ach-induced VD was potentiated by Adcy9 inactivation in femoral arteries (Emax, WT: 57.3+/-8.0%, n=11; Adcy9Gt: 84.7+/-4.2%, n=14, P<0.01). This potentiation was specific to endothelial function as endothelial-independent VD with nitroprusside was similar in WT (Emax, 70.5+/-5.7%, n=4) and Adcy9Gt (Emax, 88.2+/-5.9%, n=6) mice. Our results demonstrate that Adcy9 expression mediates the control of vascular tone in mouse femoral arteries. Adcy9 function is specific to the vascular bed studied and its expression inhibits endothelial-dependent vasodilatation and mediates that induced by β-adrenergic agonism. These findings suggest that Adcy9 function might be involved in the genotype-dependent effects of dalcetrapib on cardiovascular outcomes.
Author Disclosures: Y. Rautureau: None. P. Williams: None. M. Higgins: None. É. Thorin: None. É. Rhéaume: None. J. Tardif: Research Grant; Modest; Amarin, Eli Lilly, Isis, Merck, Pfizer, Roche, Sanofi-Aventis, Servier. Research Grant; Significant; Equity in Dalcor. Honoraria; Modest; Servier. Other; Significant; Patent genotype dependent effects of dalcetrapib.
- © 2016 by American Heart Association, Inc.