Phosphodiesterase 5 Associates With β2 Adrenergic Receptor to Modulate Cardiac Function in Type 2 Diabetic Hearts

Toni M. West, Qingtong Wang, Bingqing Deng, Yu Zhang, Federica Barbagallo, Gopireddy R. Reddy, Dana Chen, Kyle S. Phan, Bing Xu, Andres Isidori, Yang Kevin Xiang

Research output: Contribution to journalArticle

Abstract

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 β2 adrenergic receptor (β2AR), which is characterized here as a novel mechanistic axis by which sildenafil improves symptoms of diabetic cardiomyopathy. Methods and Results Wild-type and β2AR 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 β2AR, but not β1 adrenergic receptor, and inhibition of PDE5 with sildenafil restores the impaired response to adrenergic stimulation in HFD mice and isolated ventriculomyocytes. Sildenafil enhances β adrenergic receptor (βAR)-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 β2AR abolishes sildenafil's effect. Although the PDE5-β2AR association is not altered in HFD, phosphodiesterase 3 displays an increased association with the β2AR-PDE5 complex in HFD myocytes. Conclusions This study elucidates mechanisms by which the β2AR-PDE5 axis can be targeted for treating diabetic cardiomyopathy. Inhibition of PDE5 enhances β2AR stimulation of cGMP and cAMP signals, as well as protein kinase G-dependent E-C coupling in HFD myocytes.

Original languageEnglish (US)
Pages (from-to)e012273
JournalJournal of the American Heart Association
Volume8
Issue number15
DOIs
StatePublished - Aug 6 2019

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Type 5 Cyclic Nucleotide Phosphodiesterases
Adrenergic Receptors
High Fat Diet
Excitation Contraction Coupling
Diabetic Cardiomyopathies
Muscle Cells
Cyclic GMP-Dependent Protein Kinases
Calcium-Calmodulin-Dependent Protein Kinases
Energy Transfer
Phosphoric Diester Hydrolases
Cardiomegaly
Sildenafil Citrate
Cardiac Myocytes
Knockout Mice
Adrenergic Agents
Ligation
Heart Failure
Fluorescence

Keywords

  • cardiac myocyte
  • cell signaling
  • diabetic cardiomyopathy
  • EC coupling
  • echocardiography
  • pathophysiology
  • pharmacology

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Phosphodiesterase 5 Associates With β2 Adrenergic Receptor to Modulate Cardiac Function in Type 2 Diabetic Hearts. / West, Toni M.; Wang, Qingtong; Deng, Bingqing; Zhang, Yu; Barbagallo, Federica; Reddy, Gopireddy R.; Chen, Dana; Phan, Kyle S.; Xu, Bing; Isidori, Andres; Xiang, Yang Kevin.

In: Journal of the American Heart Association, Vol. 8, No. 15, 06.08.2019, p. e012273.

Research output: Contribution to journalArticle

West, TM, Wang, Q, Deng, B, Zhang, Y, Barbagallo, F, Reddy, GR, Chen, D, Phan, KS, Xu, B, Isidori, A & Xiang, YK 2019, 'Phosphodiesterase 5 Associates With β2 Adrenergic Receptor to Modulate Cardiac Function in Type 2 Diabetic Hearts', Journal of the American Heart Association, vol. 8, no. 15, pp. e012273. https://doi.org/10.1161/JAHA.119.012273
West, Toni M. ; Wang, Qingtong ; Deng, Bingqing ; Zhang, Yu ; Barbagallo, Federica ; Reddy, Gopireddy R. ; Chen, Dana ; Phan, Kyle S. ; Xu, Bing ; Isidori, Andres ; Xiang, Yang Kevin. / Phosphodiesterase 5 Associates With β2 Adrenergic Receptor to Modulate Cardiac Function in Type 2 Diabetic Hearts. In: Journal of the American Heart Association. 2019 ; Vol. 8, No. 15. pp. e012273.
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abstract = "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 β2 adrenergic receptor (β2AR), which is characterized here as a novel mechanistic axis by which sildenafil improves symptoms of diabetic cardiomyopathy. Methods and Results Wild-type and β2AR 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 β2AR, but not β1 adrenergic receptor, and inhibition of PDE5 with sildenafil restores the impaired response to adrenergic stimulation in HFD mice and isolated ventriculomyocytes. Sildenafil enhances β adrenergic receptor (βAR)-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 β2AR abolishes sildenafil's effect. Although the PDE5-β2AR association is not altered in HFD, phosphodiesterase 3 displays an increased association with the β2AR-PDE5 complex in HFD myocytes. Conclusions This study elucidates mechanisms by which the β2AR-PDE5 axis can be targeted for treating diabetic cardiomyopathy. Inhibition of PDE5 enhances β2AR stimulation of cGMP and cAMP signals, as well as protein kinase G-dependent E-C coupling in HFD myocytes.",
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author = "West, {Toni M.} and Qingtong Wang and Bingqing Deng and Yu Zhang and Federica Barbagallo and Reddy, {Gopireddy R.} and Dana Chen and Phan, {Kyle S.} and Bing Xu and Andres Isidori and Xiang, {Yang Kevin}",
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T1 - Phosphodiesterase 5 Associates With β2 Adrenergic Receptor to Modulate Cardiac Function in Type 2 Diabetic Hearts

AU - West, Toni M.

AU - Wang, Qingtong

AU - Deng, Bingqing

AU - Zhang, Yu

AU - Barbagallo, Federica

AU - Reddy, Gopireddy R.

AU - Chen, Dana

AU - Phan, Kyle S.

AU - Xu, Bing

AU - Isidori, Andres

AU - Xiang, Yang Kevin

PY - 2019/8/6

Y1 - 2019/8/6

N2 - 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 β2 adrenergic receptor (β2AR), which is characterized here as a novel mechanistic axis by which sildenafil improves symptoms of diabetic cardiomyopathy. Methods and Results Wild-type and β2AR 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 β2AR, but not β1 adrenergic receptor, and inhibition of PDE5 with sildenafil restores the impaired response to adrenergic stimulation in HFD mice and isolated ventriculomyocytes. Sildenafil enhances β adrenergic receptor (βAR)-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 β2AR abolishes sildenafil's effect. Although the PDE5-β2AR association is not altered in HFD, phosphodiesterase 3 displays an increased association with the β2AR-PDE5 complex in HFD myocytes. Conclusions This study elucidates mechanisms by which the β2AR-PDE5 axis can be targeted for treating diabetic cardiomyopathy. Inhibition of PDE5 enhances β2AR stimulation of cGMP and cAMP signals, as well as protein kinase G-dependent E-C coupling in HFD myocytes.

AB - 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 β2 adrenergic receptor (β2AR), which is characterized here as a novel mechanistic axis by which sildenafil improves symptoms of diabetic cardiomyopathy. Methods and Results Wild-type and β2AR 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 β2AR, but not β1 adrenergic receptor, and inhibition of PDE5 with sildenafil restores the impaired response to adrenergic stimulation in HFD mice and isolated ventriculomyocytes. Sildenafil enhances β adrenergic receptor (βAR)-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 β2AR abolishes sildenafil's effect. Although the PDE5-β2AR association is not altered in HFD, phosphodiesterase 3 displays an increased association with the β2AR-PDE5 complex in HFD myocytes. Conclusions This study elucidates mechanisms by which the β2AR-PDE5 axis can be targeted for treating diabetic cardiomyopathy. Inhibition of PDE5 enhances β2AR stimulation of cGMP and cAMP signals, as well as protein kinase G-dependent E-C coupling in HFD myocytes.

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KW - cell signaling

KW - diabetic cardiomyopathy

KW - EC coupling

KW - echocardiography

KW - pathophysiology

KW - pharmacology

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