title: Adenylyl cyclase 6 deletion increases mortality during sustained β-adrenergic receptor stimulation.
abstract: Sustained β-adrenergic receptor stimulation is associated with cardiomyopathy, an affect thought to result from cAMP-associated cardiac injury. Using a murine line with adenylyl cyclase 6 gene deletion (AC6KO), we tested the hypothesis that AC6 deletion, by limiting cAMP production, would attenuate cardiomyopathy in the setting of sustained β-adrenergic receptor stimulation. During 7d isoproterenol infusion, there was unexpected higher mortality in AC6KO mice compared to wild type control mice (p<0.0001). However, left ventricular function was similarly impaired in isoproterenol-infused control and AC6KO mice. There were no group differences in left ventricular hypertrophy, apoptosis, and fibrosis. Telemetric electrocardiography showed progressive prolongation of PR interval (p<0.0001), QRS duration (p<0.0005), and QTc (p<0.0001), as well as reduction in heart rate (p<0.0001), in AC6KO mice during isoproterenol infusion. These defective electrophysiological properties in isoproterenol-infused AC6KO mice were associated with decreased longitudinal ventricular conduction velocity (p<0.05) and reduced phosphorylation of connexin 43 at S368 in left ventricular samples (p=0.006). Taken together, these data demonstrate that limiting cAMP production does not prevent sustained β-adrenergic receptor stimulation-induced cardiomyopathy. Moreover, AC6 deletion impairs electrophysiological properties and increases mortality during sustained β-adrenergic receptor stimulation. Decreased connexin 43 phosphorylation and impaired ventricular conduction may be of mechanistic importance for the defective electrophysiological properties.
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA 92039, USA. ttang@zensunusa.com
authors.forename: Tong
authors.initials: T
authors.lastname: Tang
authors.forename: N Chin
authors.initials: NC
authors.lastname: Lai
authors.forename: Adam T
authors.initials: AT
authors.lastname: Wright
authors.forename: Mei Hua
authors.initials: MH
authors.lastname: Gao
authors.forename: Paul
authors.initials: P
authors.lastname: Lee
authors.forename: Tracy
authors.initials: T
authors.lastname: Guo
authors.forename: Ruoying
authors.initials: R
authors.lastname: Tang
authors.forename: Andrew D
authors.initials: AD
authors.lastname: McCulloch
authors.forename: H Kirk
authors.initials: HK
authors.lastname: Hammond
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007545:Isoproterenol / Q000009:adverse effects* / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000235:genetics / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism*; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D000318:Adrenergic beta-Agonists; D018031:Connexin 43; C543076:GJA1 protein, mouse; D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6; D007545:Isoproterenol