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. 2021 Mar:65:103251.
doi: 10.1016/j.ebiom.2021.103251. Epub 2021 Feb 24.

V体育2025版 - The role of LR-TIMAP/PP1c complex in the occurrence and development of no-reflow

Xiaoyu Quan  1 , Xiucheng Liu  2 , Xichun Qin  2 , Yuzhuo Wang  3 , Teng Sun  2 , Zhimin Li  3 , Lidong Zhu  3 , Jiali Chen  3 , Yeqing Zhou  3 , Sandeep Singh  4 , Hongyan Dong  5 , Zhongming Zhang  6 , Hao Zhang  7
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The role of LR-TIMAP/PP1c complex in the occurrence and development of no-reflow

V体育官网入口 - Xiaoyu Quan et al. EBioMedicine. 2021 Mar.

Abstract

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 VSports手机版. 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 V体育安卓版. 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. V体育ios版.

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. VSports最新版本.

Keywords: LR-TIMAP/PP1c complex; Laminin receptor; No-reflow; Phosphorylation. V体育平台登录.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no competing interests.

Figures

Image, graphical abstract
Graphical abstract
Fig. 1
Fig. 1
LR is closely related to the occurrence and severity of no-reflow in rat AMI/R models. (a) Representative images of PET perfusion imaging with 13N-NH3. The ranges selected by the dashed indicate ischemic regions after AMI or ischemic/reperfusion regions after AMI/R, n = 7. (b) Quantification of ischemic myocardial total volume. (c) Quantification of mean-standard uptake value (SUV) of the hearts. ⁎⁎P<0.01, ⁎⁎⁎P< 0.001 vs the sham group; #P<0.05, ##P<0.01; NS, P>0.05 vs the indicated group. Data are presented as means ± SEM. Statistical analysis: One-way ANOVA with Tukey post-hoc (b, c). NS, no significant difference.
Fig. 2
Fig. 2
LR promotes the stability of AJs and endothelial barrier via down-regulating phospho-Ser665-VE-cadherin. (a) Representative confocal immunofluorescence images of VE-cadherin in HCMECs with corresponding treatments, bar=5 μm. (b) Trans-well for permeability of the endothelial cell. *P<0.05 vs the normal group; #P<0.05 vs the OGD control group, n = 6. (c) Western blot analysis for the expression of membrane-VE-cad, internal-VE-cad, pS665-VE-cad. *P<0.05 vs the normal group; #P<0.05 vs the OGD control group, n = 6. (d) Western blot for membrane-VE-cad, internal-VE-cad with corresponding treatments. *P<0.05 vs the normal group; #P<0.05, △P<0.01 vs the indicated group, n = 6. Data are presented as means ± SEM. Statistical analysis: One-way ANOVA with Tukey post-hoc (b-d). AJs, adherens junctions; NS, no significant difference.
Fig. 3
Fig. 3
The phosphorylation of LR amino acid residues, Tyr 47 and Thr 125, contributes to phospho-Ser665-VE-cadherin. (a) RT-qPCR analysis for LR mRNA expression in HCMECs. (b) Verification of LR expression, NS, P>0.05 vs the indicated group, n = 6. (c) LC−MS/MS analysis for the phosphorylation residues of LR in endothelial cells. (d) Western blot analysis for the expression of pS43-LR, pY47-LR, pS75–78–79-LR and pT125-LR, ⁎⁎P<0.01 vs the respective normal group, n = 6. Statistical analysis: One-way ANOVA with Tukey post-hoc (a, b); Student's T-test (d). NS, no significant difference; pS665-VE-cad, phospho-Ser665-VE-cad.
Fig. 4
Fig. 4
Y47-LR is the upstream target site for T125-LR in the regulation of the phospho-Ser665-VE-cad-related signaling pathway. (a) Western blot analysis for the expression of LR in HCMECs with corresponding treatments. ⁎⁎P<0.01 vs the normal group; #P<0.05, NS, P>0.05 vs the indicated groups, n = 6. (b) Western blot analysis for the expressions of pS665-VE-cad and LR in OGD 4h-treated HCMECs. ##P<0.01 vs the indicated group, n = 6. (c, d) Western blot analysis for the expressions of pS665-VE-cad, pY47-LR and pT125-LR in HCMECs with corresponding treatments. *P<0.05, ⁎⁎P<0.01, ⁎⁎⁎P<0.001, #P<0.05, NS, P>0.05 vs the indicated group, n = 6. Statistical analysis: Data are presented as means ± SEM, one-way ANOVA with Tukey post-hoc (a-d). pS665-VE-cad, phospho-Ser665-VE-cad; pY47-LR, phospho-LR-Tyr47; pT125-LR, phospho-LR-Thr125; NS, no significant difference.
Fig. 5
Fig. 5
The role of PP1c and TIMAP in the regulation pT125-LR by pY47-LR. (a) Immunofluorescence for PP1c (Red) and CD31 (Green) in HCMECs. bar=10 μm. (b) Western blot analysis for the expression level of PP1c in the plasma membrane. ⁎⁎P<0.01, NS, P>0.05 vs the indicated group, n = 6. (c) Immunofluorescence staining was used to assess the localization of TIMAP (Red), bar=10 μm. (d) Western blot analysis for the expression level of TIMAP in the plasma membrane. *P<0.05, NS, P >0.05 vs the indicated group, n = 6. Statistical analysis: Data are presented as means ± SEM, one-way ANOVA with Tukey post-hoc (b, d). NS, no significant difference.
Fig.. 6
Fig.. 6
A novel LR-TIMAP/PP1c complex is responsible for the regulation of hypoxia-induced pT125-LR. (a) Immunoprecipitated analysis for the interactions between LR and TIMAP/PP1c respectively from HCMECSs lysates. Blots were probed for TIMAP and PP1c, n = 4. (b) HCMECSs were treated with LRY47D or LRY47A, then immunoprecipitated with LR antibody, n = 4. (c) Confocal immunofluorescence analysis of LR (Blue) interaction with TIMAP (Red) / PP1c (Green), Scale bar=5 μm. (d) Schematic representations in the setting of normoxia and OGD that phosphorylation or dephosphorylation of Y47-LR affects the stability of LR-TIMAP/PP1c to dephosphorylate pT125-LR. pT125-LR, phospho-LR-Thr125.
Fig. 7
Fig. 7
Low levels of pY47-LR and pT125-LR Reduce no-reflow area in vivo. (a) Representative images of PET perfusion imaging with 13N-NH3. The ranges selected by the dashed indicate ischemic regions after AMI or ischemic/reperfusion regions after AMI/R, n = 6. (b) Quantification of ischemic myocardial total volume. (c) Quantification of main Standard uptake value (SUV) mean of the hearts. *P<0.05, ⁎⁎P< 0.01 vs the AMI/R+Vector group; #P<0.05, ##P<0.01 vs the indicated group. Statistical analysis: Data are presented as means ± SEM, one-way ANOVA with Tukey post-hoc (b, c). NS, no significant difference.
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