ADCY9 (Adenylate Cyclase Type 9) Inactivation Protects From Atherosclerosis Only in the Absence of CETP (Cholesteryl Ester Transfer Protein)

Background: Pharmacogenomic studies have shown that ADCY9 genotype determines the effects of the CETP (cholesteryl ester transfer protein) inhibitor dalcetrapib on cardiovascular events and atherosclerosis imaging. The underlying mechanisms responsible for the interactions between ADCY9 and CETP activity have not yet been determined. Methods:Adcy9-inactivated (Adcy9(Gt/Gt)) and wild-type (WT) mice, that were or not transgenic for the CETP gene (CETPtgAdcy9(Gt/Gt) and CETPtgAdcy9(WT)), were submitted to an atherogenic protocol (injection of an AAV8 [adeno-associated virus serotype 8] expressing a PCSK9 [proprotein convertase subtilisin/kexin type 9] gain-of-function variant and 0.75% cholesterol diet for 16 weeks). Atherosclerosis, vasorelaxation, telemetry, and adipose tissue magnetic resonance imaging were evaluated. Results:Adcy9(Gt/Gt) mice had a 65% reduction in aortic atherosclerosis compared to WT (P<0.01). CD68 (cluster of differentiation 68)-positive macrophage accumulation and proliferation in plaques were reduced in Adcy9(Gt/Gt) mice compared to WT animals (P<0.05 for both). Femoral artery endothelial-dependent vasorelaxation was improved in Adcy9(Gt/Gt) mice (versus WT, P<0.01). Selective pharmacological blockade showed that the nitric oxide, cyclooxygenase, and endothelial-dependent hyperpolarization pathways were all responsible for the improvement of vasodilatation in Adcy9(Gt/Gt) (P<0.01 for all). Aortic endothelium from Adcy9(Gt/Gt) mice allowed significantly less adhesion of splenocytes compared to WT (P<0.05). Adcy9(Gt/Gt) mice gained more weight than WT with the atherogenic diet; this was associated with an increase in whole body adipose tissue volume (P<0.01 for both). Feed efficiency was increased in Adcy9(Gt/Gt) compared to WT mice (P<0.01), which was accompanied by prolonged cardiac RR interval (P<0.05) and improved nocturnal heart rate variability (P=0.0572). Adcy9 inactivation-induced effects on atherosclerosis, endothelial function, weight gain, adipose tissue volume, and feed efficiency were lost in CETPtgAdcy9(Gt/Gt) mice (P>0.05 versus CETPtgAdcy9(WT)). Conclusions: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, and improved endothelial function and autonomic tone.