The role of LR-TIMAP/PP1c complex in the occurrence and development of no-reflow
Xiaoyu Quan,
Xiucheng Liu,
Xichun Qin,
Yuzhuo Wang,
Teng Sun,
Zhimin Li,
Lidong Zhu,
Jiali Chen,
Yeqing Zhou,
Sandeep Singh,
Hongyan Dong,
Zhongming Zhang,
Hao Zhang
Affiliations
Xiaoyu Quan
Thoracic Surgery Laboratory, the First College of Clinical Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221006, China
Xiucheng Liu
Thoracic Surgery Laboratory, the First College of Clinical Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221006, China; Department of Thoracic Surgery, Affifiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou, Jiangsu 221006, China
Xichun Qin
Thoracic Surgery Laboratory, the First College of Clinical Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221006, China; Department of Thoracic Surgery, Affifiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou, Jiangsu 221006, China
Yuzhuo Wang
Department of Thoracic Surgery, Affifiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou, Jiangsu 221006, China
Teng Sun
Thoracic Surgery Laboratory, the First College of Clinical Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221006, China; Department of Thoracic Surgery, Affifiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou, Jiangsu 221006, China
Zhimin Li
Department of Thoracic Surgery, Affifiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou, Jiangsu 221006, China
Lidong Zhu
Department of Thoracic Surgery, Affifiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou, Jiangsu 221006, China
Jiali Chen
Department of Thoracic Surgery, Affifiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou, Jiangsu 221006, China
Yeqing Zhou
Department of Thoracic Surgery, Affifiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou, Jiangsu 221006, China
Sandeep Singh
School of International Education, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China
Hongyan Dong
Morphological Research Experiment Center, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China
Zhongming Zhang
Department of Thoracic Surgery, Affifiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou, Jiangsu 221006, China; Co-Corresponding authors.
Hao Zhang
Thoracic Surgery Laboratory, the First College of Clinical Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221006, China; Department of Thoracic Surgery, Affifiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou, Jiangsu 221006, China; Corresponding authors.
Background: The presence of no-reflow can increase the risk of major adverse cardiac events and is widely regarded as an important sign of serious prognosis. Previous studies show that laminin receptor (LR) is closely related to the morphology and function of microvessels. However, whether LR is involved in the occurrence and development of no-reflow is still unknown. Methods: In vivo, positron emission tomography (PET) perfusion imaging was performed to detect the effects of intramyocardial gene (LR-AAV and LR-siRNA-AAV) delivery treatment on the degree of no-reflow. In vitro, LC-MS/MS analysis was conducted to identify the LR phosphorylation sites of human cardiac microvascular endothelial cells (HCMECs) treated with oxygen-glucose deprivation (OGD) for 4 h. Western blot analyses were used to evaluate the phosphorylation levels of LR at residues Tyr47 (phospho-Tyr47-LR/pY47-LR) and Thr125 (phospho-Thr125-LR/pT125-LR) and their effects on the phosphorylation of VE-cadherin residue Ser665 (phospho-Ser665-VE-cad). Findings: LR over-expression, LRT125A (phosphonull) and LRY47A (phosphonull) treatments were found to reduce the level of phospho-Ser665-VE-cad, and subsequently maintain adherent junctions and endothelial barrier integrity in hypoxic environments. Mechanistically, TIMAP/PP1c can combine with LR on the cell membrane to form a novel LR-TIMAP/PP1c complex. The level of pY47-LR determined the stability of LR-TIMAP/PP1c complex. The binding of TIMAP/PP1c on LR activated the protein phosphatase activity of PP1c and regulated the level of pT125-LR. Interpretation: This study demonstrates that low level of phospho-LR reduces no-reflow area through stabilizing the LR-TIMAP/PP1c complex and promoting the stability of adherens junctions, and may help identify new therapeutic targets for the treatment of no-reflow.