Upregulation of anticoagulant proteins, protein S and tissue factor pathway inhibitor, in the mouse myocardium with cardio-specific TNF-α overexpression

Abstract

<jats:p>Heart failure (HF) has been recognized as a hypercoagulable state. However, the natural anticoagulation systems in the failing heart have not been studied. Recent experimental and clinical data have indicated that not only the thrombomodulin (TM)/protein C (PC) pathway but also the protein S (PS)/tissue factor pathway inhibitor (TFPI) system function as potent natural anticoagulants. To investigate the balance between procoagulant and anticoagulant activities in the failing heart, we measured the cardiac expression of tissue factor (TF), type 1 plasminogen activator inhibitor (PAI-1), TM, PC, PS, and TFPI by RT-PCR and/or Western blot analysis in male transgenic (TG) mice with heart-specific overexpression of TNF-α. Both procoagulant (TF and PAI-1) and anticoagulant (PS and TFPI) factors were upregulated in the myocardium of 24-wk-old TG (end-stage HF) but not in that of 4-wk-old TG (early decompensated HF) compared with the wild-type mice. Both factors were also upregulated in the infarcted myocardium at 3 days after coronary ligation in the wild-type mice. The expression of TM was downregulated in the TG heart, and PC was not detected in the hearts. The transcript levels of PS orphan receptors, Mer and Tyro3, but not Axl, were significantly upregulated in the TG heart. Double immunohistochemical staining revealed that myocardial infiltrating CD3-positive T cells may produce PS in the TG myocardium. In conclusion, the PS/TFPI was upregulated in the myocardium of a different etiological model of HF, thus suggesting a role for the PS/TFPI system in the protection of the failing heart under both inflammatory and hypercoagulable states.</jats:p>

The Gas6/TAM System and Multiple Sclerosis

“…Tyro3 predominates in mouse and human central nervous systems (CNS) [16,17], but it is also expressed by platelets [18], the heart [19], ovaries and testis [20], breasts [21], osteoclasts [22], and the retina [23]. Axl is widely expressed in many tissues and organs, including the brain [24], liver [25], kidney [26], heart [19], monocytes/macrophages [27], and endothelial [28] and vascular smooth muscle cells [29].…”

“…Tyro3 predominates in mouse and human central nervous systems (CNS) [16,17], but it is also expressed by platelets [18], the heart [19], ovaries and testis [20], breasts [21], osteoclasts [22], and the retina [23]. Axl is widely expressed in many tissues and organs, including the brain [24], liver [25], kidney [26], heart [19], monocytes/macrophages [27], and endothelial [28] and vascular smooth muscle cells [29]. Finally, MerTK is the main mediator of Gas6 activity on immune cells [30,31], but is also expressed by the brain [24], platelets [32], gonads and prostate [33,34], lung [35], retina [23], kidney [36], and heart [19].…”

Correlation of Coagulation Pathway Parameters with BNP, Ejection Fraction and NYHA Class in Heart Failure

“…It has been postulated using animal models such as the murine system that increase in the anticoagulation parameters is a protective mechanism in heart failure in the setting of hypercoagulable and pro inflammatory states [17]. The other explanation for increased anticoagulation is the dysfunction of the right ventricle and passive congestion of the liver that follows.…”

Proteomic biomarkers of recovered heart function

“…20 -22 Higuchi et al 23 found that protein S was upregulated in mouse myocardium in different aetiological models of HF, and hypothesized that this up-regulation may have a protective role in the failing heart. 23 A recent review by Mongirdiene et al 22 highlighted coagulation factors V and VII as being altered in HF; however, the roles in HF of coagulation factors IX and X, from the RHF biomarker panel, are presently unclear. The enrichment of coagulation-related proteins in the RHF panel suggests that this pathway could well play a much larger role in HF, particularly in protective or recovery processes, than currently thought.…”