Inhibiting insulin-mediated β 2-adrenergic receptor activation prevents diabetes-associated cardiac dysfunction

Qingtong Wang, Yongming Liu, Qin Fu, Bing Xu, Yuan Zhang, Sungjin Kim, Ruensern Tan, Federica Barbagallo, Toni West, Ethan Anderson, Wei Wei, E. Dale Abel, Yang Kevin Xiang

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Background: Type 2 diabetes mellitus (DM) and obesity independently increase the risk of heart failure by incompletely understood mechanisms. We propose that hyperinsulinemia might promote adverse consequences in the hearts of subjects with type-2 DM and obesity. Methods: High-fat diet feeding was used to induce obesity and DM in wild-type mice or mice lacking β 2 -adrenergic receptor (β 2 AR) or β-arrestin2. Wild-type mice fed with high-fat diet were treated with a β-blocker carvedilol or a GRK2 (G-protein-coupled receptor kinase 2) inhibitor. We examined signaling and cardiac contractile function. Results: High-fat diet feeding selectively increases the expression of phosphodiesterase 4D (PDE4D) in mouse hearts, in concert with reduced protein kinase A phosphorylation of phospholamban, which contributes to systolic and diastolic dysfunction. The expression of PDE4D is also elevated in human hearts with DM. The induction of PDE4D expression is mediated by an insulin receptor, insulin receptor substrate, and GRK2 and β-arrestin2-dependent transactivation of a β 2 AR-extracellular regulated protein kinase signaling cascade. Thus, pharmacological inhibition of β 2 AR or GRK2, or genetic deletion of β 2 AR or β-arrestin2, all significantly attenuate insulin-induced phosphorylation of extracellular regulated protein kinase and PDE4D induction to prevent DM-related contractile dysfunction. Conclusions: These studies elucidate a novel mechanism by which hyperinsulinemia contributes to heart failure by increasing PDE4D expression and identify β 2 AR or GRK2 as plausible therapeutic targets for preventing or treating heart failure in subjects with type 2 DM.

Original languageEnglish (US)
Pages (from-to)73-88
Number of pages16
JournalCirculation
Volume135
Issue number1
DOIs
StatePublished - Jan 3 2017

Fingerprint

Type 4 Cyclic Nucleotide Phosphodiesterase
G-Protein-Coupled Receptor Kinase 2
Adrenergic Receptors
Insulin
High Fat Diet
Type 2 Diabetes Mellitus
Diabetes Mellitus
Heart Failure
Obesity
Hyperinsulinism
Protein Kinases
Phosphorylation
Insulin Receptor Substrate Proteins
Insulin Receptor
Cyclic AMP-Dependent Protein Kinases
Transcriptional Activation
Pharmacology

Keywords

  • diabetic cardiomyopathy
  • heart failure
  • insulin
  • phosphodiesterase
  • β-adrenergic receptors

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Inhibiting insulin-mediated β 2-adrenergic receptor activation prevents diabetes-associated cardiac dysfunction. / Wang, Qingtong; Liu, Yongming; Fu, Qin; Xu, Bing; Zhang, Yuan; Kim, Sungjin; Tan, Ruensern; Barbagallo, Federica; West, Toni; Anderson, Ethan; Wei, Wei; Abel, E. Dale; Xiang, Yang Kevin.

In: Circulation, Vol. 135, No. 1, 03.01.2017, p. 73-88.

Research output: Contribution to journalArticle

Wang, Q, Liu, Y, Fu, Q, Xu, B, Zhang, Y, Kim, S, Tan, R, Barbagallo, F, West, T, Anderson, E, Wei, W, Abel, ED & Xiang, YK 2017, 'Inhibiting insulin-mediated β 2-adrenergic receptor activation prevents diabetes-associated cardiac dysfunction', Circulation, vol. 135, no. 1, pp. 73-88. https://doi.org/10.1161/CIRCULATIONAHA.116.022281
Wang, Qingtong ; Liu, Yongming ; Fu, Qin ; Xu, Bing ; Zhang, Yuan ; Kim, Sungjin ; Tan, Ruensern ; Barbagallo, Federica ; West, Toni ; Anderson, Ethan ; Wei, Wei ; Abel, E. Dale ; Xiang, Yang Kevin. / Inhibiting insulin-mediated β 2-adrenergic receptor activation prevents diabetes-associated cardiac dysfunction. In: Circulation. 2017 ; Vol. 135, No. 1. pp. 73-88.
@article{9807f3bdcaa34377913ac4a64424c319,
title = "Inhibiting insulin-mediated β 2-adrenergic receptor activation prevents diabetes-associated cardiac dysfunction",
abstract = "Background: Type 2 diabetes mellitus (DM) and obesity independently increase the risk of heart failure by incompletely understood mechanisms. We propose that hyperinsulinemia might promote adverse consequences in the hearts of subjects with type-2 DM and obesity. Methods: High-fat diet feeding was used to induce obesity and DM in wild-type mice or mice lacking β 2 -adrenergic receptor (β 2 AR) or β-arrestin2. Wild-type mice fed with high-fat diet were treated with a β-blocker carvedilol or a GRK2 (G-protein-coupled receptor kinase 2) inhibitor. We examined signaling and cardiac contractile function. Results: High-fat diet feeding selectively increases the expression of phosphodiesterase 4D (PDE4D) in mouse hearts, in concert with reduced protein kinase A phosphorylation of phospholamban, which contributes to systolic and diastolic dysfunction. The expression of PDE4D is also elevated in human hearts with DM. The induction of PDE4D expression is mediated by an insulin receptor, insulin receptor substrate, and GRK2 and β-arrestin2-dependent transactivation of a β 2 AR-extracellular regulated protein kinase signaling cascade. Thus, pharmacological inhibition of β 2 AR or GRK2, or genetic deletion of β 2 AR or β-arrestin2, all significantly attenuate insulin-induced phosphorylation of extracellular regulated protein kinase and PDE4D induction to prevent DM-related contractile dysfunction. Conclusions: These studies elucidate a novel mechanism by which hyperinsulinemia contributes to heart failure by increasing PDE4D expression and identify β 2 AR or GRK2 as plausible therapeutic targets for preventing or treating heart failure in subjects with type 2 DM.",
keywords = "diabetic cardiomyopathy, heart failure, insulin, phosphodiesterase, β-adrenergic receptors",
author = "Qingtong Wang and Yongming Liu and Qin Fu and Bing Xu and Yuan Zhang and Sungjin Kim and Ruensern Tan and Federica Barbagallo and Toni West and Ethan Anderson and Wei Wei and Abel, {E. Dale} and Xiang, {Yang Kevin}",
year = "2017",
month = "1",
day = "3",
doi = "10.1161/CIRCULATIONAHA.116.022281",
language = "English (US)",
volume = "135",
pages = "73--88",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

TY - JOUR

T1 - Inhibiting insulin-mediated β 2-adrenergic receptor activation prevents diabetes-associated cardiac dysfunction

AU - Wang, Qingtong

AU - Liu, Yongming

AU - Fu, Qin

AU - Xu, Bing

AU - Zhang, Yuan

AU - Kim, Sungjin

AU - Tan, Ruensern

AU - Barbagallo, Federica

AU - West, Toni

AU - Anderson, Ethan

AU - Wei, Wei

AU - Abel, E. Dale

AU - Xiang, Yang Kevin

PY - 2017/1/3

Y1 - 2017/1/3

N2 - Background: Type 2 diabetes mellitus (DM) and obesity independently increase the risk of heart failure by incompletely understood mechanisms. We propose that hyperinsulinemia might promote adverse consequences in the hearts of subjects with type-2 DM and obesity. Methods: High-fat diet feeding was used to induce obesity and DM in wild-type mice or mice lacking β 2 -adrenergic receptor (β 2 AR) or β-arrestin2. Wild-type mice fed with high-fat diet were treated with a β-blocker carvedilol or a GRK2 (G-protein-coupled receptor kinase 2) inhibitor. We examined signaling and cardiac contractile function. Results: High-fat diet feeding selectively increases the expression of phosphodiesterase 4D (PDE4D) in mouse hearts, in concert with reduced protein kinase A phosphorylation of phospholamban, which contributes to systolic and diastolic dysfunction. The expression of PDE4D is also elevated in human hearts with DM. The induction of PDE4D expression is mediated by an insulin receptor, insulin receptor substrate, and GRK2 and β-arrestin2-dependent transactivation of a β 2 AR-extracellular regulated protein kinase signaling cascade. Thus, pharmacological inhibition of β 2 AR or GRK2, or genetic deletion of β 2 AR or β-arrestin2, all significantly attenuate insulin-induced phosphorylation of extracellular regulated protein kinase and PDE4D induction to prevent DM-related contractile dysfunction. Conclusions: These studies elucidate a novel mechanism by which hyperinsulinemia contributes to heart failure by increasing PDE4D expression and identify β 2 AR or GRK2 as plausible therapeutic targets for preventing or treating heart failure in subjects with type 2 DM.

AB - Background: Type 2 diabetes mellitus (DM) and obesity independently increase the risk of heart failure by incompletely understood mechanisms. We propose that hyperinsulinemia might promote adverse consequences in the hearts of subjects with type-2 DM and obesity. Methods: High-fat diet feeding was used to induce obesity and DM in wild-type mice or mice lacking β 2 -adrenergic receptor (β 2 AR) or β-arrestin2. Wild-type mice fed with high-fat diet were treated with a β-blocker carvedilol or a GRK2 (G-protein-coupled receptor kinase 2) inhibitor. We examined signaling and cardiac contractile function. Results: High-fat diet feeding selectively increases the expression of phosphodiesterase 4D (PDE4D) in mouse hearts, in concert with reduced protein kinase A phosphorylation of phospholamban, which contributes to systolic and diastolic dysfunction. The expression of PDE4D is also elevated in human hearts with DM. The induction of PDE4D expression is mediated by an insulin receptor, insulin receptor substrate, and GRK2 and β-arrestin2-dependent transactivation of a β 2 AR-extracellular regulated protein kinase signaling cascade. Thus, pharmacological inhibition of β 2 AR or GRK2, or genetic deletion of β 2 AR or β-arrestin2, all significantly attenuate insulin-induced phosphorylation of extracellular regulated protein kinase and PDE4D induction to prevent DM-related contractile dysfunction. Conclusions: These studies elucidate a novel mechanism by which hyperinsulinemia contributes to heart failure by increasing PDE4D expression and identify β 2 AR or GRK2 as plausible therapeutic targets for preventing or treating heart failure in subjects with type 2 DM.

KW - diabetic cardiomyopathy

KW - heart failure

KW - insulin

KW - phosphodiesterase

KW - β-adrenergic receptors

UR - http://www.scopus.com/inward/record.url?scp=84997040259&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84997040259&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.116.022281

DO - 10.1161/CIRCULATIONAHA.116.022281

M3 - Article

C2 - 27815373

AN - SCOPUS:84997040259

VL - 135

SP - 73

EP - 88

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 1

ER -