Protective and pathological roles of tissue factor in the heart

Summary

Tissue factor (TF) is expressed in the heart where it is required for haemostasis. High levels of TF are also expressed in atherosclerotic plaques and likely contribute to atherothrombosis after plaque rupture. Indeed, risk factors for atherothrombosis, such as diabetes, hypercholesterolaemia, smoking and hypertension, are associated with increased TF expression in circulating monocytes, microparticles and plasma. Several therapies that reduce atherothrombosis, such as statins, ACE inhibitors, beta-blockers and anti-platelet drugs, are associated with reduced TF expression. In addition to its haemostatic and pro-thrombotic functions, the TF : FVIIa complex and downstream coagulation proteases activate cells by cleavage of protease-activated receptors (PARs). In mice, deficiencies in either PAR-1 or PAR-2 reduce cardiac remodelling and heart failure after ischaemia-reperfusion injury. This suggests that inhibition of coagulation proteases and PARs may be protective in heart attack patients. In contrast, the TF/thrombin/ PAR-1 pathway is beneficial in a mouse model of Coxsackievirus B3-induced viral myocarditis. We found that stimulation of PAR-1 increases the innate immune response by enhancing TLR3-dependent IFN-_ expression. Therefore, inhibition of the TF/thrombin/PAR-1 pathway in patients with viral myocarditis could have detrimental effects. Conclusion: The TF : FVIIa complex has both protective and pathological roles in the heart.

Zusammenfassung

Tissue Factor (TF, Faktor III, Gewebsthromboplastin) wird im Herzen exprimiert, wo er für die effektive Hämostase benötigt wird. TF wird auch in atherosklerotischen Plaques exprimiert und trägt sehr wahrscheinlich zur Atherothrombose nach Plaque-ruptur bei. Risikofaktoren für Atherothrombose, wie Diabetes mellitus, Hypercholesterinämie, Rauchen und Bluthochdruck sind mit erhöhter TF-Expression auf zirkulierenden Monozyten, Mikropartikeln und im Plasma assoziiert. Therapien gegen Atherothrombose (z. B. Statine, ACEHemmer, Betablocker und Plättcheninhibitoren) sind mit reduzierter TF-Expression assoziiert. Zusätzlich zu den hämostatischen und pro-thrombotischen Funktionen aktiviert der TF : FVIIa-Komplex zusammen mit nachgeschalteten Gerinnungsfaktoren Zellen durch Aktivierung von Protease-aktivierten Rezeptoren (PARs). In PAR-1- und PAR-2-defizienten Mäusen ist das kardiale Remodelling und die Herzinsuffizienz nach einem kardialen Reperfusionsschaden reduziert. Folglich könnte eine Inhibition von Gerinnungsfaktoren und PARs positive Effekte in Herzinfarkt- Patienten haben. Im Gegensatz dazu ist die Aktivierung des TF/Thrombin/PAR-1-Signalweges in einem Mausmodell von Coxsackievirus- B3-induzierter Myokarditis von Vorteil. Unsere Ergebnisse zeigen, dass die Stimulierung von PAR-1 die angeborene Immunantwort durch TLR3-abhängige Interferon-Expression verstärkt. Demzufolge könnte die Inhibition des TF/Thrombin/PAR-1-Signalweges in Patienten mit viraler Myokarditis fatale Folgen haben. Schlussfolgerung: Die Daten weisen darauf hin, dass der TF : FVIIa-Komplex im Herzen abhängig vom Krankheitsbild sowohl protektive als auch pathologische Eigenschaften vermitteln kann.

Keywords

Tissue factor - haemostasis - atherothrombosis - cardiac remodelling

Schlüsselwörter

Tissue Factor - Hämostase - Atherothrombose - Kardiales Remodelling

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