Abstract 624: Interactions Between Adenylate Cyclase Type 9 (ADCY9) and Cholesteryl Ester Transfer Protein (CETP) in Atherosclerosis

Autor: Géraldine Miquel, Vanessa Deschambault, Marie-Claude Guertin, Pascale Geoffroy, Sylvie Levesque, Eric Rhéaume, Mélanie Mecteau, Marie-Ève Higgins, Kurunradeth Uy, Marc-Antoine Gillis, Yohann Rautureau, Samaneh Samami, Foued Maafi, Pierre-Marc Williams, Maria-Laura Suarez, David Rhainds, Adeline Raignault, Mathieu R. Brodeur, Eric Thorin, Rocio Sanchez, Philippe Pouliot, Line Lapointe, Daniel Rivas, Audrey Nault, Jean-Claude Tardif, Natacha Duquette, Geneviève Brand, Marie-Pierre Dubé, Gaétan Mayer
Rok vydání: 2018
Předmět:
Zdroj: Arteriosclerosis, Thrombosis, and Vascular Biology. 38
ISSN: 1524-4636
1079-5642
Popis: Pharmacogenomic studies have shown that ADCY9 genotype determines the effects of the cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib on cardiovascular events, atherosclerosis imaging and body weight variation. The underlying mechanisms responsible for the interactions between ADCY9 and CETP have not yet been determined. Adcy9 -inactivated ( Adcy9 Gt/Gt ) and wild-type (WT) mice, that were or not transgenic for the CETP gene (CETP Gt and CETP WT ), were submitted to an atherogenic protocol (injection of an AAV8 expressing a PCSK9 gain-of-function variant and 0.75% cholesterol diet for 16 weeks). Atherosclerosis, cell adhesion, vasorelaxation, telemetry and adipose tissue MRI were evaluated. Adcy9 Gt/Gt mice had a 65% reduction in aortic atherosclerosis compared to WT ( P Adcy9 Gt/Gt mice compared to WT animals ( P Adcy9 inactivation did not change counts of blood monocytes and their subsets. Splenocytes showed reduced adhesion to native aortic endothelium from Adcy9 Gt/Gt mice ( P Adcy9 Gt/Gt mice (versus WT, P Adcy9 Gt/Gt versus WT ( P Adcy9 Gt/Gt mice gained more weight than WT with the atherogenic diet, and this was associated with an increase in whole body adipose tissue volume ( P Adcy9 Gt/Gt compared to WT mice ( P P =0.0572) and prolonged cardiac RR interval ( P Adcy9 inactivation-induced effects on atherosclerosis, endothelium-dependent vasodilation, weight gain and feed efficiency were lost in CETP Gt mice ( P >0.05 vs CETP WT ). Adcy9 inactivation protects against atherosclerosis, but only in the absence of CETP activity. This atheroprotection may be explained by decreased macrophage accumulation and proliferation in the arterial wall, improved endothelial function and autonomic tone.
Databáze: OpenAIRE
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