Dudley Lab

Unfolded Protein Response and Arrhythmias

Human heart failure is characterized by arrhythmogenic electrical remodeling consisting mostly of ion channel downregulations. Understanding the pathophysiological mechanisms of arrhythmias is crucial for finding the proper treatments. Adult cardiomyocytes, being differentiated and lack of regenerative potential, require a vital balance of its contents such as sarcomeres, membrane ion channel proteins, and mitochondria to maintain its viability and function. Therefore, protein quality control is crucial for cardiomyocyte survival and function. The unfolded protein response (UPR) is one of the important mechanisms of protein quality control in the endoplasmic reticulum (ER) to monitor and regulate misfolded and unfolded proteins. Our group has found that the activated UPR in human heart failure plays important roles on downregulation of cardiac Nav1.5. Recently, we reported that the UPR regulates multiple cardiac ion channels under ER stress in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), indicating an arrhythmogenic role of the UPR in heart disease. Activated UPR is also observed in our mouse models of ischemic and nonischemic heart failure. In preliminary study, we found that inhibiting PERK after myocardial infarction reduced sudden death, reduced spontaneous, nonsustained ventricular tachycardia, reduced QTc interval, and reduced action potential duration without negative consequences to contractile function.

Our studies and literature show that the UPR plays important roles in heart and targeting the UPR seems to be a potentially fruitful approach and clinically beneficial in novel therapeutics for cardiac disease. We will keep investigating the mechanisms of the beneficial effects of PERK inhibition and if the IRE1 and ATF6 branches play important roles in heart failure.

Mg and High Fat Diet-Induced Diabetes

Increased consumption of a high-fat diet (HFD) and a sedentary lifestyle have been implicated in the global epidemic of obesity. Obesity and diabetes mellitus (DM) are important risk factors for the development of cardiovascular disease, including cardiac diastolic dysfunction (DD). Cardiac DD underlies heart failure with preserved ejection fraction. Altered myocardial metabolism and increased oxidative stress accompany DM-associated DD. Recently, we have reported that cardiac mitochondrial oxidative stress can cause DD and heart failure with preserved ejection fraction by oxidatively modifying cardiac myosin binding protein C.

Magnesium (Mg) is an essential element for mitochondrial function, especially for ATP production. Mg deficiency is found commonly in cardiovascular disease, type II DM, hypertension, heart failure, and ventricular arrhythmia patients. A low serum Mg level is associated with increased cardiovascular mortality, while dietary Mg intake is associated with a decreased risk of developing type II DM and heart failure.

Our recent study shows that oral Mg supplementation improve mitochondrial function and cardiac DD/hypertrophy in a HFD mouse model of type II DM. Therefore, dietary Mg supplementation may be an inexpensive therapy for DD and subsequent heart failure with preserved ejection fraction. We will keep investigating the mechanisms of how Mg reverses cardiac DD/hypertrophy and mitochondrial dysfunction.

The Contribution of Mitochondrial Ca2+ Handling to Arrhythmia in Heart Failure

Recently, we have shown that mitochondrial Ca2+ handling can play roles in automaticity, action potential prolongation, and triggered arrhythmias. This suggests that mitochondrial dysfunction may be a central process in the generation of arrhythmias in cardiac disease and that altering mitochondrial Ca2+ flux may be a new therapeutic antiarrhythmic target.

Molecular Mechanisms of Sodium Channel (SCN5A) Regulation in Heart Disease

Downregulated sodium currents in heart failure (HF) has been linked to increased arrhythmic risk. Various factors may be contribute to the downregulation of sodium channel gene SCN5A mRNA. Currently, we are focusing on the role of alternative splicing factors and 3' UTR mediated mRNA stability factors in regulation of SCN5A. Furthermore, we are studying the role of specific miRNA on regulation of SCN5A in hypoxia which is a common pathogenic factor in HF. This allows us to build and understand the gene network for SCN5A regulatory and identify targets that may be applied to therapy.

Full list of publications at Experts@Minnesota.

1. Xie A, Gallant B, Guo H, Gonzalez A, Clark M, Madigan A, Feng F, Chen HD, Cui Y, Dudley SC Jr, Wan Y. Functional cardiac Na(+) channels are expressed in human melanoma cells. Oncol Lett. 2018 Aug;16(2):1689-1695.
2. Xie A, Zhou A, Liu H, Shi G, Liu M, Boheler KR, Dudley SC Jr. Mitochondrial. Ca2+ flux modulates spontaneous electrical activity in ventricular cardiomyocytes. PLoS One. 2018 Jul 12;13(7):e0200448.
3. Zhou A, Shi G, Kang GJ, Xie A, Liu H, Jiang N, Liu M, Jeong EM, Dudley SC Jr. RNA Binding Protein, HuR, Regulates SCN5A Expression Through Stabilizing MEF2C transcription factor mRNA. J Am Heart Assoc. 2018 Apr 20;7(9).
4. Xie A, Song Z, Liu H, Zhou A, Shi G, Wang Q, Gu L, Liu M, Xie LH, Qu Z, Dudley SC Jr. Mitochondrial Ca(2+) Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy. J Am Heart Assoc. 2018 Apr 7;7(8).
5. Liu M, Shi G, Zhou A, Rupert CE, Coulombe KLK, Dudley SC Jr. Activation of the unfolded protein response downregulates cardiac ion channels in human induced pluripotent stem cell-derived cardiomyocytes. J Mol Cell Cardiol. 2018 Apr;117:62-71.
6. Zhang X, Yoon JY, Morley M, McLendon JM, Mapuskar KA, Gutmann R, Mehdi H, Bloom HL, Dudley SC, Ellinor PT, Shalaby AA, Weiss R, Tang WHW, Moravec CS, Singh M, Taylor AL, Yancy CW, Feldman AM, McNamara DM, Irani K, Spitz DR, Breheny P, Margulies KB, London B, Boudreau RL. A common variant alters SCN5A-miR-24 interaction and associates with heart failure mortality. J Clin Invest. 2018 Mar 1;128(3):1154-1163.
7. Zhou A, Xie A, Kim TY, Liu H, Shi G, Kang GJ, Jiang N, Liu M, Jeong EM, Choi BR, Dudley SC Jr. HuR-mediated SCN5A messenger RNA stability reduces arrhythmic risk in heart failure. Heart Rhythm. 2018 Jul;15(7):1072-1080.
8. Noyes AM, Zhou A, Gao G, Gu L, Day S, Andrew Wasserstrom J, Dudley SC. Abnormal sodium channel mRNA splicing in hypertrophic cardiomyopathy. Int J Cardiol. 2017 Dec 15;249:282-286.
9. Vang A, Clements RT, Chichger H, Kue N, Allawzi A, O'Connell K, Jeong EM, Dudley SC Jr, Sakhatskyy P, Lu Q, Zhang P, Rounds S, Choudhary G. Effect of α7 nicotinic acetylcholine receptor activation on cardiac fibroblasts: a mechanism underlying RV fibrosis associated with cigarette smoke exposure. Am J Physiol Lung Cell Mol Physiol. 2017 May 1;312(5):L748-L759.
10. Kim TY, Terentyeva R, Roder KH, Li W, Liu M, Greener I, Hamilton S, Polina I, Murphy KR, Clements RT, Dudley SC Jr, Koren G, Choi BR, Terentyev D. SK channel enhancers attenuate Ca2+-dependent arrhythmia in hypertrophic hearts by regulating mito-ROS-dependent oxidation and activity of RyR. Cardiovasc Res. 2017 Mar 1;113(3):343-353.

Full list of publications at Experts@Minnesota.

Principal Investigator: Sam Dudley, M.D., Ph.D.

Professorof Medicine
Director, Lillehei Heart Institute
Chief, Cardiovascular Division
Fred C. and Katherine B. Andersen Chair - Adult Cardiology

Hong Liu, Ph.D.

Assistant Professor

Man Liu, Ph.D.

Assistant Professor
Joined the Lab: January, 2001
Education:

• 2003 Ph.D - Biophysics - Johann Wolfgang Goethe-Universität/Institut für Biophysik
• 2000 MS - Biophysics - Nankai University
• 1997 BS - Biophysics - Nankai University

Research Interests: My research focuses on three projects.  One is TRPM7 regulation on atrial fibrillation. TRPM7 is a Mg2+ transporter and could be a trigger for inflammation activation, mitochondrial ROS overproduction, and ER dysfunction in diabetes mellitus-associated AF. The second is magnesium deficiency on cardiac diastolic function (DD) and heart failure with preserved ejection fraction (HFpEF) by using a high fat diet-induced diabetic mouse model and a low-Mg diet-induced hypomagnesemia (HypoMg) mouse model. TRPM7 kinase plays a key role in HypoMg-mediated HFpEF.  The third project is mitochondrial dysfunction in cardiac diastolic dysfunction on a diabetic mouse model.  Mitochondrial targeted antioxidants have been tested in the diabetic mouse model to reverse cardiac diastolic dysfunction and future tests on larger animals are planned.  The third project is the unfolded protein response and arrhythmias. Studies of electrophysiology, gene/protein expression, and in vivo animal tests show that the unfolded protein response mainly downregulates cardiac ion channels, causing electrical remodeling in ischemic heart failure.
Accomplishments:

• 2023 - Abstract Oral presentation in the American Heart Association Scientific Sessions, Philadelphia PA, USA
• 2022 - Abstract Oral presentation in the XVI International Magnesium Symposium "Magnesium in Health & Disease", Glasgow, Scotland, UK
• 2019 - Abstract Oral presentation in the XV International Magnesium Symposium – Magnesium in Health and Disease, Bethesda, Maryland, USA
• 2018 - Abstract Oral presentation in the 37th Annual Meeting of the North Amerian Section of the International Soceity for Heart Research, Halifax, Nova Scotia, Canada
• 2016 - Abstract Oral presentation in the Heart Rhythm Society Annual meeting, San Francisco, CA, USA
• 2013 - Abstract Oral presentation in the Heart Rhythm Society Annual meeting, Denver, CO, USA
• 2013 - Abstract Oral Abstract Award winner, the Combined Annual Meeting of Central Society of Clinical and Translational Research and Midwestern Section American Federation of Medical Research, Chicago, IL, USA
• 2010 - Abstract Oral presentation in the 54th Annual Meeting of Biophysical Society, San Francisco, CA, USA
• 2009 - Abstract Oral presentation in the American Heart Association Scientific sessions, Orlando, FL, USA
• 2003 - Abstract Oral presentation in the 10th European Conference on the Spectroscopy of Biological Molecules, Szeged, Hungary
• 1999 - Boehringer Scholarship, Leipzig/Jena, Germany

Contact: liu00290@umn.edu

An Xie, Ph.D. 

Research Assistant Professor
Joined the Lab: January, 2011
Education:

• 1995 PhD. - Cardiovascular physiology - Fourth Military Medical University 
• 1987 B.S. -   Biomedical Engineering - Xi'an Jiao Tong University

Research Interests: Cardiomyocyte organellous calcium handling and cardac arrhythmia
Accomplishments: 

• 2023 - Lysosomal Ca2+-flux contributes to abnormal automaticity related arrhythmia in ventricular cardiomyopathy. Biophysical Society 67nd Annual Meeting, San Diego, California. 
• 2023 -Lysosomal Ca2+ flux modulates automaticity in ventricular cardiomyocytes and correlates with arrhythmic risk, PNAS Nexus. 2023 Jun; 2(6): pgad174.

Contact: axie@umn.edu

Gyeoung-Jin Kang, Ph.D.

Post-doctoral Associate