Increased Enzyme Activity and β-Adrenergic–Mediated Vasodilation in Subjects Expressing a Single-Nucleotide Variant of Human Adenylyl Cyclase 6

Abstract

Objective— cAMP is a critical regulator of metabolic and cardiovascular function. However, the role of genetic variability in the regulation of cAMP-mediated effects is unclear. Therefore, we assessed the effect of the expression of a recently identified missense genetic variant of adenylyl cyclase isoform 6 (ADCY6 S674). Methods and Results— In rat vascular smooth muscle cells, gene transfer of ADCY6 S674 increased adenylyl cyclase activity and arborization to a greater extent than gene transfer of ADCY6 A674. Similarly, in adherent mononuclear leukocyte cells isolated from ADCY6 S674-expressing human subjects, both adenylyl cyclase activity and adenylyl cyclase–mediated cell retraction were significantly increased. Additionally, in dorsal hand vein LVDT studies, subjects expressing the hyper-functional ADCY6 S674 variant had significantly greater vascular sensitivity to the β-adrenergic agonist isoproterenol as assessed by both a greater potency and greater maximal effect than subjects expressing the ADCY6 A674 enzyme. Conclusion— These data indicate that the expression of a novel, relatively common variant of ADCY6 parallels an increase in adenylyl cyclase activity and adenylyl cyclase–mediated function in humans.