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

Abstract Introduction 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 implicated in cardiac injuries and dysfunction, the contribution of its cytoplasmic domain in cardiac pathology remains unclear. Purpose We aimed to investigate the contribution of the cytoplasmic domain of TF to post-infarct myocardial injury and adverse left ventricular (LV) remodeling. Methods and results Myocardial infarction was induced by permanent occlusion of the left anterior descending coronary artery. Male mice with C57BL/Jax background were used for the study. Compared with wild-type mice, mice lacking the TF cytoplasmic domain (TFΔCT) had a higher survival rate (90.5% versus 70%, p=0.0298) during a 28-day follow-up after myocardial infarction. Among surviving mice, TFΔCT mice had better cardiac function and less LV remodeling (ESV: 114.5±13.1mL for WT, 67.06±10.8mL for TFΔCT, p<0.001; EDV: 146.6±12.4mL for WT, 99.97±11.71mL for TFΔCT, p<0.001) than wild-type mice. Bone marrow chimerism indicated that deletion of the TF cytoplasmic domain in either bone marrow-derived cells or cardiac resident cells could alleviate post-infarct cardiac dysfunction. Speckle-tracking strain analysis revealed that the overall improvement of post-infarct cardiac performance in TFΔCT mice was attributed to reduced myocardial deformation in the peri-infarct region (strain-%: 11.14±0.97 for WT, 15.34±1.10 for TFΔCT, p=0.007; strain rate-/s: 3.89±0.26 for WT, 5.18±0.21 for TFΔCT, p=0.0005). Histological analysis demonstrated that TFΔCT hearts had in the infarct area greater proliferation of endothelial cells and myofibroblasts accompanied with better scar formation. Compared with wild-type hearts, infarcted TFΔCT hearts showed less infiltration of proinflammatory cells with concomitant lower expression of protease-activated receptor-1 (PAR1)-Rac1 axis. Furthermore, infarcted TFΔCT 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. 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. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): National University Health System of Singapore