Interleukin-1β, Oxidative Stress, and Abnormal Calcium Handling Mediate Diabetic Arrhythmic Risk

Hong Liu; Yang Zhao; An Xie; Tae-Yun Kim; Radmila Terentyeva; Man Liu; Guangbin Shi; Feng Feng; Bum-Rak Choi; Dmitry Terentyev; Shanna Hamilton; Samuel C Dudley Jr

doi:10.1016/j.jacbts.2020.11.002

Interleukin-1β, Oxidative Stress, and Abnormal Calcium Handling Mediate Diabetic Arrhythmic Risk

JACC Basic Transl Sci. 2021 Jan 20;6(1):42-52. doi: 10.1016/j.jacbts.2020.11.002. eCollection 2021 Jan.

Authors

Hong Liu¹, Yang Zhao², An Xie¹, Tae-Yun Kim³, Radmila Terentyeva^{3

4}, Man Liu¹, Guangbin Shi³, Feng Feng¹, Bum-Rak Choi³, Dmitry Terentyev^{3

4}, Shanna Hamilton⁴, Samuel C Dudley Jr¹

Affiliations

¹ Division of Cardiology, Department of Medicine, Lillehei Heart Institute, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA.
² Division of Cardiology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China.
³ Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
⁴ Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio, USA.

Abstract

Diabetes mellitus (DM) is associated with increased arrhythmia. Type 2 DM (T2DM) mice showed prolonged QT interval and increased ventricular arrhythmic inducibility, accompanied by elevated cardiac interleukin (IL)-1β, increased mitochondrial reactive oxygen species (mitoROS), and oxidation of the sarcoplasmic reticulum (SR) Ca²⁺ release channel (ryanodine receptor 2 [RyR2]). Inhibiting IL-1β and mitoROS reduced RyR2 oxidation and the ventricular arrhythmia in DM. Inhibiting SR Ca2⁺ leak by stabilizing the oxidized RyR2 channel reversed the diabetic arrhythmic risk. In conclusion, cardiac IL-1β mediated the DM-associated arrhythmia through mitoROS generation that enhances SR Ca²⁺ leak. The mechanistic link between inflammation and arrhythmias provides new therapeutic options.

Keywords: APD, action potential duration; DM, diabetes mellitus; EAD, early afterdepolarization; IL, interleukin; IL-1RA, interleukin-1 receptor antagonist; Ito, transient outward potassium current; RyR2, ryanodine receptor; SR, sarcoplasmic reticulum; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; VT, ventricular tachycardia; calcium handling; inflammation; mitoROS, mitochondrial reactive oxygen species; mitochondria; oxidation; sudden cardiac death.

Abstract

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