L'adénylate cyclase de type 9 favorise le développement de l'athérosclérose chez la souris
A pharmacogenomic study recently showed that polymorphisms in the ADCY9 gene determine the clinical response to the cholesterol ester transfer protein (CETP) inhibitor dalcetrapib in patients suffering from atherosclerosis. Theses variants controlling dalcetrapib response had no effect in patients treated on placebo, suggesting interaction between ADCY9 and CETP activity. The study revealed that dalcetrapib was associated with change in body weight. We then investigated the role of Adcy9 in atherosclerosis development and in lipid metabolism in interaction with CETP. Mice inactivated for Adcy9 showed a 65% reduction in the development of atherosclerosis lesions compared to WT. Atheroprotection in Adcy9-inactivated mice was associated with a protection of endothelial function and a reduced accumulation of foam cells in the atherosclerotic lesion of the vascular wall. Metabolic study during atherosclerosis demonstrated that Adcy9 controls body weight and fat metabolism. These results were associated with an increase in feed efficiency when Adcy9 was inactivated and a modulation of the SNA activity. In transgenic mice expressing CETP, the atheroprotection resulting from Adcy9 inactivation was lost. Atherosclerosis development and body weight variation were the same between mice groups. We concluded that Adcy9 inactivation protects against atherosclerosis, but only in the absence of CETP activity. These results in mice support our pharmacogenomic discovery in patients and emphasize the interaction between of CETP activity and ADCY9 function in the treatment of patients suffering from atherosclerosis.
Adénylate cyclase Adcy9 CETP Atherosclerosis adenylyl cyclase mice