Theranostics 2021; 11(19):9243-9261. doi:10.7150/thno.63354 This issue

Research Paper

Tissue factor cytoplasmic domain exacerbates post-infarct left ventricular remodeling via orchestrating cardiac inflammation and angiogenesis

Suet Yen Chong1,2*, Olga Zharkova1,2*, Siti Maryam J.M. Yatim1,2, Xiaoyuan Wang1,2, Xiong Chang Lim2, Chenyuan Huang1,2, Chia Yee Tan2,3, Jianming Jiang2,3, Lei Ye4, Michelle Siying Tan1, Veronique Angeli5,6, Henri H. Versteeg7, Mieke Dewerchin8,9, Peter Carmeliet8,9, Carolyn S.P. Lam10,11, Mark Y. Chan2,12, Dominique P.V. de Kleijn13,14, Jiong-Wei Wang1,2,15,16✉

1. Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
2. Cardiovascular Research Institute (CVRI), Cardiovascular Disease TRP, National University Heart Centre Singapore (NUHCS), Singapore, Singapore
3. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
4. National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore.
5. Immunology translational research program, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore,
6. Immunology Program, Life Sciences Institute, National University of Singapore, Singapore
7. Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Centre, The Netherlands
8. Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB, Leuven, Belgium.
9. Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
10. National Heart Centre Singapore (NHCS), Duke-NUS Graduate Medical School, Singapore, Singapore.
11. Department of Cardiology, University Medical Center, Groningen, The Netherlands.
12. Department of Medicine, Yong Loo Lin School of Medicine, Singapore, Singapore.
13. Netherlands Heart Institute, Utrecht, the Netherlands.
14. Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.
15. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
16. Nanomedicine translational research programme, Centre for NanoMedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
*These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Chong SY, Zharkova O, Yatim SMJM, Wang X, Lim XC, Huang C, Tan CY, Jiang J, Ye L, Tan MS, Angeli V, Versteeg HH, Dewerchin M, Carmeliet P, Lam CSP, Chan MY, de Kleijn DPV, Wang JW. Tissue factor cytoplasmic domain exacerbates post-infarct left ventricular remodeling via orchestrating cardiac inflammation and angiogenesis. Theranostics 2021; 11(19):9243-9261. doi:10.7150/thno.63354. Available from https://www.thno.org/v11p9243.htm

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Abstract

Graphic abstract

The coagulation protein tissue factor (TF) regulates inflammation and angiogenesis via its cytoplasmic domain in infection, cancer and diabetes. While TF is highly abundant in the heart and is implicated in cardiac pathology, the contribution of its cytoplasmic domain to post-infarct myocardial injury and adverse left ventricular (LV) remodeling remains unknown.

Methods: Myocardial infarction was induced in wild-type mice or mice lacking the TF cytoplasmic domain (TF∆CT) by occlusion of the left anterior descending coronary artery. Heart function was monitored with echocardiography. Heart tissue was collected at different time-points for histological, molecular and flow cytometry analysis.

Results: Compared with wild-type mice, TF∆CT had a higher survival rate during a 28-day follow-up after myocardial infarction. Among surviving mice, TF∆CT mice had better cardiac function and less LV remodeling than wild-type mice. The overall improvement of post-infarct cardiac performance in TF∆CT mice, as revealed by speckle-tracking strain analysis, was attributed to reduced myocardial deformation in the peri-infarct region. Histological analysis demonstrated that TF∆CT hearts had in the infarct area greater proliferation of myofibroblasts and better scar formation. Compared with wild-type hearts, infarcted TF∆CT hearts showed less infiltration of proinflammatory cells with concomitant lower expression of protease-activated receptor-1 (PAR1) - Rac1 axis. In particular, infarcted TF∆CT hearts displayed markedly lower ratios of inflammatory M1 macrophages and reparative M2 macrophages (M1/M2). In vitro experiment with primary macrophages demonstrated that deletion of the TF cytoplasmic domain inhibited macrophage polarization toward the M1 phenotype. Furthermore, infarcted TF∆CT hearts presented markedly higher peri-infarct vessel density associated with enhanced endothelial cell proliferation and higher expression of PAR2 and PAR2-associated pro-angiogenic pathway factors. Finally, the overall cardioprotective effects observed in TF∆CT mice could be abolished by subcutaneously infusing a cocktail of PAR1-activating peptide and PAR2-inhibiting peptide via osmotic minipumps.

Conclusions: Our findings demonstrate that the TF cytoplasmic domain exacerbates post-infarct cardiac injury and adverse LV remodeling via differential regulation of inflammation and angiogenesis. Targeted inhibition of the TF cytoplasmic domain-mediated intracellular signaling may ameliorate post-infarct LV remodeling without perturbing coagulation.

Keywords: tissue factor cytoplasmic domain, myocardial infarction, inflammation, angiogenesis, adverse left ventricular remodeling