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PKCβ/NF-κB pathway in diabetic atrial remodeling

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Abstract

Atrial remodeling in diabetes is partially attributed to NF-κB/TGF-β signal transduction pathway activation. We examined whether the hyperglycemia-induced increased expression of NF-κB/TGF-β was dependent upon protein kinase C-β (PKCβ) and tested the hypothesis that selective inhibition of PKCβ using ruboxistaurin (RBX) can reduce NF-κB/TGF-β expression and inhibit abnormal atrial remodeling in streptozotocin (STZ)–induced diabetic rats. The effects of PKCβ inhibition on NF-κB/TGF-β signal transduction pathway-mediated atrial remodeling were investigated in STZ-induced diabetic rats. Mouse atrial cardiomyocytes (HL-1 cells) were cultured in low- or high-glucose or mannitol conditions in the presence or absence of small interference RNA that targeted PKCβ. PKCβ inhibition using ruboxistaurin (RBX, 1 mg/kg/day) decreased the expression of NF-κBp65, p-IκB, P38MARK, TNF-α, TGF-β, Cav1.2, and NCX proteins and inducibility of atrial fibrillation (AF) in STZ-induced diabetic rats. Exposure of cardiomyocytes to high-glucose condition activated PKCβ and increased NF-κB/TGF-β expression. Suppression of PKCβ expression by small interference RNA decreased high-glucose–induced NF-κB and extracellular signal–related kinase activation in HL-1 cells. Pharmacological inhibition of PKCβ is an effective method to reduce AF incidence in diabetic rat models by preventing NF-κB/TGF-β-mediated atrial remodeling.

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Data availability

All data generated or analyzed during this study are included in this published article.

Abbreviations

NF-κB:

nuclear factor kappaB

TGF-β:

transforming growth factor-β

PKCβ:

protein kinase C-β

STZ:

streptozotocin

RBX:

ruboxistaurin

AF:

atrial fibrillation

DM:

diabetes mellitus

DAG:

diacylglycerol

LAD:

left atrial anteroposterior diameter

LVEDD:

left ventricular end-diastolic diameter

LVESD:

left ventricular end-systolic diameter

LVEF:

left ventricular ejection fraction

SBP:

systolic blood pressure

DBP:

diastolic blood pressure

MBP:

mean blood pressure

LVEDP:

left ventricular end-diastolic pressure

RA:

right atrium

LA:

left atrium

RV:

right ventricle

IACT:

interatrial conduction time

AVWCL:

Wenckebach cycle length of AV conduction

PCL:

pace cycle length

AERP:

atrial effective refractory period

AERPD:

atrial effective refractory period dispersion

FPG:

fasting plasma glucose

IKK:

IκB kinase

MAPK:

mitogen-activated protein kinase

NCX:

Na+-Ca2+ exchanger current

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Funding

This study was funded by grants to H.F. from the Tianjin Natural Science Foundation (16JCYBJC25000), Key Laboratory Scientific Research Foundation of Second Hospital of Tianjin Medical University (2018ZDSYS03), and Clinical Study of Second Hospital of Tianjin Medical University (2019LC03) and grants (81570298 and 81970270 to T.L.) from the National Natural Science Foundation of China.

Author information

Author notes

  1. Haili Wang, Yuanyuan Xu and Aiqing Xu contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, 300211, People’s Republic of China

    Haili Wang, Yuanyuan Xu, Aiqing Xu, Xinghua Wang, Lijun Cheng, Gary Tse, Guangping Li, Tong Liu & Huaying Fu

  2. Beijing Capital International Airport Hospital, Beijing, People’s Republic of China

    Haili Wang

  3. Shenzhen Research Institute, Chinese University of Hong Kong, Hong Kong, SAR, People’s Republic of China

    Sharen Lee

Authors
  1. Haili Wang
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  4. Xinghua Wang
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  9. Tong Liu
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Contributions

Huaying Fu: conception of the work and design of experiments; Haili Wang and Yuanyuan Xu: collection, analysis of data, and drafting of the manuscript; Xinghua Wang, Tong Liu, Aiqing Xu, and Lijun Cheng: recorded and analyzed the experimental data; Huaying Fu, Sharen Lee, Gary Tse, and Guangping Li: data interpretation and critically revised the manuscript.

Corresponding authors

Correspondence to Tong Liu or Huaying Fu.

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The authors declare that they have no competing interests.

Ethics approval and consent to participate

This study was approved by the Experimental Animal Administration Committee of Tianjin Medical University and Tianjin Municipal Commission for Experimental Animal Control.

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Key points

• Diabetes-activated PKCβ/NF-κB pathway causes atrial structural remodeling.

• PKCβ/NF-κB pathway activation changed Na+-Ca2+ exchanger current in diabetes.

• Atrial remodeling can be prevented by PKCβ inhibition using ruboxistaurin (RBX).

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Cite this article

Wang, H., Xu, Y., Xu, A. et al. PKCβ/NF-κB pathway in diabetic atrial remodeling. J Physiol Biochem 76, 637–653 (2020). https://doi.org/10.1007/s13105-020-00769-7

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