Altered membrane currents are implicated in sudden cardiac death. Ischemic cardiomyopathy (ICM) is responsible for three quarters of these deaths. In preliminary data, we show that (i) PERK, part of the unfolded protein response (UPR), is activated early and persistently in a mouse myocardial infarct (MI) model, (ii) inhibiting PERK after MI reduces sudden death, reduces spontaneous, nonsustained ventricular tachycardia (VT), reduces QTc interval, and reduces action potential duration (APD) without negative consequences to contractile function, (iii) the UPR activation prolongs APD, slows AP upstroke, and alters some but not all ion channels, and (iv) PERK inhibition partially reversed APD prolongation and some ion channel downregulations. Hypothesis: We hypothesize that activation of PERK and other UPR sensors reduce mRNA abundance and protein translation of cardiac ion channels. This contributes to current alterations, APD prolongation, and increased arrhythmic risk in ICM. Inhibition of PERK or other UPR effectors can prevent some of the remodeling. In vivo, PERK inhibition will be antiarrhythmic in ICM, in part, by improving conduction velocity and reducing APD.
Specific aims :
Aim 1 : Determine the extent to which PERK inhibition can prevent APD prolongation, electrical remodeling and arrhythmic risk associated with ICM. In this aim, ICM will be induced in mice. APD, electrical remodeling and arrhythmic risk will be compared between mice with and without pharmacological inhibition of PERK starting immediate after infarct or at 3 weeks to test prevention versus treatment strategies. Results will be compared to genetic inhibition of PERK (cardiac specific PERK-knockout (KO)) and to findings in human ICM.
Aim 2 : Determine the extent to which PERK can contribute to APD prolongation and the alterations of ion channels. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with activated UPR, we will determine which other ion channels are altered by UPR and PERK activation and are responsible for APD prolongation.
Aim 3 : Investigate whether the IRE1 and ATF6? branches of the UPR contribute to APD prolongation and the alterations of ion channels. Using hiPSC-CMs and activating the IRE1 and ATF6? branches of UPR, we will determine whether activation of these two branches contributes to AP changes and downregulation of cardiac ion channels.

Public Health Relevance

Heart failure is occurring at near epidemic portions worldwide. Heart failure is associated with sudden cardiac death because of ion channel changes. This application will determine the importance of the unfolded protein response in these changes and potentially develop new therapies for sudden death.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL134791-03
Application #
9729803
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Balijepalli, Ravi C
Project Start
2017-08-01
Project End
2021-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Liu, Man; Dudley Jr, Samuel C (2018) The role of the unfolded protein response in arrhythmias. Channels (Austin) 12:335-345
Liu, Man; Shi, Guangbin; Zhou, Anyu et al. (2018) Activation of the unfolded protein response downregulates cardiac ion channels in human induced pluripotent stem cell-derived cardiomyocytes. J Mol Cell Cardiol 117:62-71