Abstract:
Background: Atrial fibrillation (AF) is the most common form of arrhythmia and is a growing clinical problem. Post-translational modifications (PTMs) constitute crucial epigenetic mechanisms but modification of lysine 2-hydroxyisobutyrylation (Khib) in AF is still unknown. This study aimed to investigate the role and mechanism of Khib in AF.
Methods: PTM proteomics was applied in the human atrial tissue from AF and sinus rhythm patients with heart valve disease during cardiac surgery to identify the Khib sites. The functional changes of differential modification sites were further validated at the cellular level. Cellular electrophysiology was performed to record the ion channel current and action potential duration (APD).
Results: The modification of 124 Khib sites in 35 proteins and 67 sites in 48 proteins exhibited significant increase or decrease in AF compared to sinus rhythm. Ten Khib sites were included in energy metabolism-related signaling pathways (HXK1, TPIS, PGM1, and OPDX in glycolysis; MDHC and IDH3A in tricarboxylic acid circle; NDUS2, ETFB, ADT3, and ATPB in oxidative respiratory chain). Importantly, decreased HXK1 K418hib regulated by HDAC2 attenuated the original chemical binding domain between HXK1 and glucose, inhibited the binding ability between HXK1 and glucose, and reduced catalytic ability of the enzyme, resulting in low production of glucose-6-phosphate and ATP. Further, it also increased Kir6.2 protein and the current of KATP channel, and decreased APD.
Conclusions: This study demonstrates the importance of Khib to catalysis of HXK1 and reveals molecular mechanisms of HXK1 K418hib in AF, providing new insight into strategies of AF.
Biography:
Professor Guo-Wei HE, MD, PhD, DSc, is Distinguished Professor of Tianjin University, China and Academician (Foreign Correspondence Member) at The National Academy of Medicine, France (2019-). Professor He is Vice President & Senior Cardiac Surgeon at TEDA International Cardiovascular Hospital, Tianjin University and Director of Institute for Cardiovasc Diseases, Tianjin University & Chinese Academy of Medical Sciences. He also holds Clinical Professor of Surgery at Oregon Health & Science University, Portland, OR, USA (2003-). In addition, Professor He is Director, Branch Center for National Clinical Research Center for Cardiovascular Disease and Director of Tianjin Key Laboratory for Molecular Regulation and Translational Medicine of Cardiovascular Diseases He obtained Doctor of Science (2003) and Ph. D.(1989) from Monash University, Melbourne, Australia.
Professor He was Chair Professor of Cardiothoracic Surgery, University of Hong Kong, 1995-2000 and Research Chair Professor, Chinese University of Hong Kong (2000-2009). Professor He was Director of Cardiovasc Res Lab, St, Vincent Hospital, Portland, OR, U.S.A. (1994-2012). Professor He is an active cardiac surgeon and he performed nearly 8,000 open heart operations. Notably, he is the first surgeon performing radial artery plus internal mammary artery in CABG at University of Hong Kong in Asia (1995) and is well known for “He Classification” and “He solutions” for CABG grafts. Apart from clinical practice, he is an active research and obtained more than 80 research grants and awards such as First Class Award, Tianjin Municipal Natural Science Award (2012), First Class Award, Prize of Science & Technology, The China Medicine Education Association (2021), exec. He published 415 articles/reports in SCI-index international journals.
He ranks the top 0.05% of all scholars worldwide (ScholarGPS), World's Top 2% Scientists (2019-2024) by Stanford University and H-index (57) of world top 1%. Professor He ranks world’s top 1% in Medicine, Chemistry, Genetics and Molecular Biology; He is Highly-cited Chinese Scholar in Clinical Medicine (Elsevier 2024).
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