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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2657.)
© 2007 American Heart Association, Inc.

Vascular Biology

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

Robert Gros; Stan Van Uum; Adam Hutchinson-Jaffe; Qingming Ding; J. Geoffrey Pickering; Robert A. Hegele; Ross D. Feldman

From the Departments of Medicine (S.V.U., A.H.J., J.G.P., R.A.H., R.D.F.) and of Physiology & Pharmacology (R.G., R.D.F.), University of Western Ontario, and Cell Biology (Q.D., R.D.F.) and Vascular Biology (R.G., J.G.P., R.A.H.) Research Groups, Robarts Research Institute, London, Ontario, Canada.

Correspondence to Dr Ross D. Feldman, Robarts Research Institute, P.O. Box 5015, 100 Perth Drive, London, Ontario, Canada, N6A 5K8. E-mail feldmanr{at}lhsc.on.ca

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.

We examined the phenotypic characteristics of an adenylyl cyclase 6 (ADCY6 S674) variant in human subjects and isolated human mononuclear leukocytes and rat smooth muscle cells. Our data demonstrate that expression of this ADCY6 S674 variant is associated with enhanced adenylyl cyclase activity and enhanced cAMP-mediated regulation of contractile responses.

Key Words: smooth muscle • adenylyl cyclase • vasodilation