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Adenylyl cyclase 6 deletion increases mortality during sustained ?-adrenergic receptor stimulation.


ABSTRACT: Sustained ?-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 ?-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 ?-adrenergic receptor stimulation-induced cardiomyopathy. Moreover, AC6 deletion impairs electrophysiological properties and increases mortality during sustained ?-adrenergic receptor stimulation. Decreased connexin 43 phosphorylation and impaired ventricular conduction may be of mechanistic importance for the defective electrophysiological properties.

SUBMITTER: Tang T 

PROVIDER: S-EPMC3987812 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Adenylyl cyclase 6 deletion increases mortality during sustained β-adrenergic receptor stimulation.

Tang Tong T   Lai N Chin NC   Wright Adam T AT   Gao Mei Hua MH   Lee Paul P   Guo Tracy T   Tang Ruoying R   McCulloch Andrew D AD   Hammond H Kirk HK  

Journal of molecular and cellular cardiology 20130412


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 (  ...[more]

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