期刊
JOURNAL OF THE AMERICAN HEART ASSOCIATION
卷 8, 期 15, 页码 -出版社
WILEY
DOI: 10.1161/JAHA.119.012273
关键词
cardiac myocyte; cell signaling; diabetic cardiomyopathy; EC coupling; echocardiography; pathophysiology; pharmacology
资金
- NIH [R01-HL127764, R01-HL112413]
- US Veteran's Administration Merit grant [01BX002900]
- American Heart Association
Background-In murine heart failure models and in humans with diabetic-related heart hypertrophy, inhibition of phosphodiesterase 5 (PDE5) by sildenafil improves cardiac outcomes. However, the mechanism by which sildenafil improves cardiac function is unclear. We have observed a relationship between PDE5 and beta 2 adrenergic receptor (beta 2AR), which is characterized here as a novel mechanistic axis by which sildenafil improves symptoms of diabetic cardiomyopathy. Methods and Results-Wild-type and beta 2AR knockout mice fed a high fat diet (HFD) were treated with sildenafil, and echocardiogram analysis was performed. Cardiomyocytes were isolated for excitation-contraction (E-C) coupling, fluorescence resonant energy transfer, and proximity ligation assays; while heart tissues were implemented for biochemical and histological analyses. PDE5 selectively associates with beta 2AR, but not beta 1 adrenergic receptor, and inhibition of PDE5 with sildenafil restores the impaired response to adrenergic stimulation in HFD mice and isolated ventriculomyocytes. Sildenafil enhances beta adrenergic receptor (beta AR)-stimulated cGMP and cAMP signals in HFD myocytes. Consequently, inhibition of PDE5 leads to protein kinase G-, and to a lesser extent, calcium/calmodulin-dependent kinase II-dependent improvements in adrenergically stimulated E-C coupling. Deletion of beta 2AR abolishes sildenafil's effect. Although the PDE5-beta 2AR association is not altered in HFD, phosphodiesterase 3 displays an increased association with the beta 2AR-PDE5 complex in HFD myocytes. Conclusions-This study elucidates mechanisms by which the beta 2AR-PDE5 axis can be targeted for treating diabetic cardiomyopathy. Inhibition of PDE5 enhances beta 2AR stimulation of cGMP and cAMP signals, as well as protein kinase G-dependent E-C coupling in HFD myocytes.
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