Title : Post-translational modifications of proteins in cardiovascular diseases

Protein post-translational modifications, particularly reversible lysine acylation, have emerged as critical arbiters of cardiac homeostasis and disease. Our group has systematically employed quantitative PTM proteomics to elucidate the roles of propionylation, crotonylation, and 2-hydroxyisobutyrylation in human atrial fibrillation, coronary artery bypass graft failure, and cardiac hypertrophy. These studies uncover precise molecular mechanisms through which site-specific acyl modifications dictate cardiac energetics, redox balance, and electrophysiology, offering novel therapeutic targets.

In patients developing new-onset postoperative atrial fibrillation following coronary bypass surgery, we constructed the first lysine propionylome of human right atrium. We discovered that propionylation of ALDH6A1 at Lys113 is elevated 2.25-fold, which enhances its binding to NAD?, elevates NADH levels, and drives reactive oxygen species accumulation. This ALDH6A1-NADH-ROS axis creates a pro-arrhythmic oxidative environment that promotes the initiation of postoperative atrial fibrillation.

To address the differential long-term patency of arterial versus venous coronary grafts, we performed paired crotonylome analysis of internal thoracic artery and saphenous vein segments from 150 patients. Vein grafts demonstrated significantly higher crotonylation levels on the anti-oxidative enzymes thioredoxin (K3), glyoxalase 1 (K157), and GAPDH (K61), which depressed their enzymatic activities, leading to methylglyoxal accumulation and severe oxidative stress. Strikingly, pharmacological inhibition of the crotonyltransferase CBP or overexpression of the decrotonylases HDAC1/3 restored enzyme function and mitigated oxidative damage. These findings demonstrate that epigenetic modulation of crotonylation could “arterialize” vein grafts to improve long-term patency.

In chronic atrial fibrillation, we mapped the 2-hydroxyisobutyrylome of human atrial tissue and identified decreased 2-hydroxyisobutyrylation of hexokinase 1 at K418. This modification impairs glucose binding and glycolytic flux, reducing ATP production. The resultant energy deficit upregulates the KATP channel subunit Kir6.2, enhances KATP current, and shortens atrial action potential duration, thereby directly coupling a single PTM site to the electrical remodeling that sustains the arrhythmia.

Using Sirt1 cardiac-specific knockout mice, we demonstrated that loss of this deacylase causes hypercrotonylation of SERCA2a at Lys120. The modification weakens ATP binding, depresses sarcoplasmic reticulum calcium re uptake, and precipitates cardiac hypertrophy, systolic dysfunction, and arrhythmias. This mechanism illustrates how a defect in PTM eraser activity can translate into profound structural and functional heart disease.

Collectively, these investigations establish that site-specific lysine acylations function as molecular switches on key metabolic, anti-oxidative, and ion-handling proteins, directly governing cardiac pathophysiology. The regulatory enzymes—sirtuins, CBP/p300, and HDACs—emerge as tractable therapeutic targets. Our comprehensive review further details how the crosstalk among diverse acylations (acetylation, crotonylation, propionylation, lactylation, malonylation, succinylation, and lipidation) drives cardiac hypertrophy through chromatin remodeling and metabolic reprogramming, highlighting the promise of isoform-specific enzyme modulators. These insights pave the way for PTM-directed precision medicine strategies—including small-molecule agents and gene-editing approaches that precisely target individual acylation sites—to combat atrial fibrillation, vein graft disease, and heart failure.

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).