The National Science and Technology Council (NSTC) has been constantly promoting basic and translational research, supporting domestic researchers to carry out various scientific research, pursue academic excellence, and explore the causes of diseases and their diagnosis and treatment strategies, and thus creating scientific and technological breakthroughs to benefit the people. On the basis of the long-term support of the Frontier Science Research Program of the Department of Life Sciences of NSTC, this outstanding research accomplishment was achieved by an interdisciplinary team led by Dr. Jeng-Jiann Chiu, Dean of the College of Medical Science and Technology of Taipei Medical University and Distinguished Investigator of the National Health Research Institutes, who discovered for the first time a novel molecular target critical for the diagnosis and treatment of atherosclerosis. This outstanding research achievement was published in the top international prestigious journal "European Heart Journal" on November 16 this year, and has received extensive attention from related international fields.
Atherosclerosis is an important medical problem in Taiwan and worldwide, which leads to significant incidence of cardiovascular diseases, causing a serious social and economic burden. Clinical observations reveal that atherosclerosis preferentially develops in arterial branches and curvatures, where the blood flow is very complex, often causing disturbed flow with low and oscillatory shear stress (OSS). This disturbed flow with OSS is proposed to be the main cause of early development of atherosclerosis. However, the detailed mechanisms by which disturbed flow with OSS induces early development of atherosclerosis remain unclear. Through a combination of state-of-the-art technologies including porcine models, large-scale phosphoproteomics, tissue-specific transgenic mice, and clinical specimens, Chiu’s team has discovered a novel atherosclerosis-related phosphoprotein vinculin (VCL) with disturbed flow-induced phosphorylation at serine 721 (VCLS721p). This induction of VCLS721p was mediated by G-protein-coupled receptor kinase 2 (GRK2) and resulted in an inactive form of VCL with a closed conformation, leading to the VE-cadherin/catenin complex disruption to enhance endothelial permeability and atherogenesis. Studies on clinical specimens from patients with coronary artery disease (CAD) revealed that endothelial VCLS721p is a critical clinicopathological biomarker for atherosclerosis progression and that serum VCLS721p level is a promising biomarker for CAD diagnosis. The findings of this study indicate that endothelial VCLS721p is a valuable hemodynamic-based target for clinical assessment and treatment of vascular disorders resulting from atherosclerosis. Such information has provided new insights into the mechanisms by which disturbed flow promotes atherosclerosis development and may generate new therapeutic approaches for early diagnosis and intervention for atherosclerosis and their complications.
Chiu’s team has long-term collaboration with internationally renowned research institutions and universities in Taiwan and abroad, including Academia Sinica, National Taiwan University, Tri-Service General Hospital, China Medical University, and the Department of Bioengineering and Institute of Engineering in Medicine at the University of California, San Diego. This innovative scientific research achievement is a concrete manifestation of long-term collaboration with these domestic and foreign research institutions and universities.
Figure Caption: Proposed mechanisms by which disturbed flow induces vinculin phosphorylation at serine 721 (VCLS721p) in vascular endothelium, leading to atherosclerosis. A combination of porcine models, large-scale phosphoproteomics, transgenic mice, and clinical specimens was used to demonstrate that disturbed flow induces endothelial VCLS721p via G-protein-coupled receptor kinase 2 (GRK2), resulting in an inactive form of VCL with a closed conformation. This disrupted the VE-cadherin junction/catenin complex to enhance endothelial permeability and atherosclerosis. Statin therapy was associated with reduced levels of VCLS721p and VCLS721p/VCL in the serum of patients with coronary artery disease. AJs: adherens junctions.
Author Information:
Jeng-Jiann Chiu, Ph.D.
Dean and Chair Professor of Vascular Molecular Bioengineering
College of Medical Science and Technology, Taipei Medical University
Distinguished Investigator
Institute of Cellular and System Medicine, National Health Research Institutes