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

Autor: Peter Carmeliet, Xiong Chang Lim, Mark Y Chan, Chenyuan Huang, Mieke Dewerchin, Siti Maryam J M Yatim, Carolyn S.P. Lam, Dominique P.V. de Kleijn, Michelle Siying Tan, Xiaoyuan Wang, Jiong-Wei Wang, Olga Zharkova, Veronique Angeli, Lei Ye, Jianming Jiang, Suet Yen Chong, Henri H. Versteeg, Chia Yee Tan
Přispěvatelé: Cardiovascular Centre (CVC)
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Male
Pathology
Angiogenesis
FACTOR VIIA
Medicine (miscellaneous)
ISCHEMIA-REPERFUSION INJURY
Research & Experimental Medicine
Ventricular Function
Left
Mice
angiogenesis
Fibrosis
Medicine
FIBROSIS
Myocytes
Cardiac
Myocardial infarction
Myofibroblasts
Pharmacology
Toxicology and Pharmaceutics (miscellaneous)
FACTOR DEFICIENCY
Neovascularization
Pathologic
Ventricular Remodeling
tissue factor cytoplasmic domain
RECEPTOR 2
myocardial infarction
Medicine
Research & Experimental
cardiovascular system
medicine.symptom
Life Sciences & Biomedicine
Signal Transduction
Research Paper
medicine.medical_specialty
TARGETED DELETION
Macrophage polarization
INHIBITION
Inflammation
Thromboplastin
Proinflammatory cytokine
Tissue factor
Protein Domains
adverse left ventricular remodeling
EXTRACELLULAR-MATRIX
Animals
Receptor
PAR-2
Receptor
PAR-1
Ventricular remodeling
Cell Proliferation
Science & Technology
business.industry
Macrophages
Myocardium
Macrophage Activation
medicine.disease
COLLAGEN
Mice
Inbred C57BL
MYOCARDIAL-INFARCTION
inflammation
business
Zdroj: Theranostics
Theranostics, 11(19), 9243-9261. IVYSPRING INT PUBL
ISSN: 1838-7640
Popis: 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 increment 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 increment CT had a higher survival rate during a 28-day follow-up after myocardial infarction. Among surviving mice, TF increment CT mice had better cardiac function and less LV remodeling than wild-type mice. The overall improvement of post-infarct cardiac performance in TF increment 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 increment CT hearts had in the infarct area greater proliferation of myofibroblasts and better scar formation. Compared with wild-type hearts, infarcted TF increment CT hearts showed less infiltration of proinflammatory cells with concomitant lower expression of protease-activated receptor-1 (PAR1) -Rac1 axis. In particular, infarcted TF increment 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 increment 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 increment 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.
Databáze: OpenAIRE
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