Viral myocarditis and coagulopathy: Increased tissue factor expression and plasma thrombogenicity

Antoniak, Silvio; Boltzen, Ulrike; Riad, Alexander; Kallwellis-Opara, Angela; Rohde, Maria; Dörner, Andrea; Tschöpe, Carsten; Noutsias, Michel; Pauschinger, Matthias; Schultheiss, Heinz‐Peter; Rauch, Ursula

doi:10.1016/j.yjmcc.2008.03.013

Cited by 44 publications

(61 citation statements)

References 41 publications

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“…Virus infection is associated with TF-dependent activation of coagulation and the generation of thrombin, the major activator of PAR-1 in vivo (12)(13)(14)(15)(16)(17). Previously, we found that TF protein expression was increased in…”

Section: Resultsmentioning

confidence: 98%

“…We observed lower levels of Ifnb1 mRNA expression in the hearts of Par1 -/-compared with Par1 +/+ mice at 2 dpi ( Figure 1C Par1 -/-mice have increased inflammation in the heart at 8 dpi. CVB3 infection leads to inflammation and infiltration of immune cells into the heart (14). We hypothesized that the higher level of CVB3 at 8 dpi observed in Par1 -/-mice will evoke a higher level of inflammation and infiltration of immune cells.…”

Section: Resultsmentioning

confidence: 98%

“…CVB3-induced myocarditis leads to cardiac injury and heart failure (14). We used plasma cardiac troponin I as a measure of cardiac injury.…”

Section: Resultsmentioning

confidence: 99%

“…Heart function analysis by echocardiography before CVB3 infection and at 28 dpi the hearts of CVB3-infected WT mice at 8 dpi, and this was associated with increased fibrin deposition (14). In this study, we analyzed levels of Tf mRNA expression in the heart and the activation of coagulation in the circulation of WT mice at different times after CVB3 infection.…”

Section: Tablementioning

confidence: 99%

“…In addition, coagulation proteases can activate cells by cleavage of PARs (8)(9)(10). Bacterial and viral infections induce TF expression on various cell types, including monocytes and endothelial cells (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Bacterial LPS induces TF expression in monocytes and endothelial cells via activation of TLR4 (21)(22)(23), whereas the TLR3 agonist polyinosinic:polycytidylic acid (poly I:C) induces TF expression in endothelial cells, but not monocytes (17).…”

Section: Introductionmentioning

confidence: 99%

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PAR-1 contributes to the innate immune response during viral infection

Antoniak¹,

Owens²,

Baunacke³

et al. 2013

J. Clin. Invest.

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132

227

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Coagulation is a host defense system that limits the spread of pathogens. Coagulation proteases, such as thrombin, also activate cells by cleaving PARs. In this study, we analyzed the role of PAR-1 in coxsackievirus B3-induced (CVB3-induced) myocarditis and influenza A infection. CVB3-infected Par1 -/-mice expressed reduced levels of IFN-β and CXCL10 during the early phase of infection compared with Par1 +/+ mice that resulted in higher viral loads and cardiac injury at day 8 after infection. Inhibition of either tissue factor or thrombin in WT mice also significantly increased CVB3 levels in the heart and cardiac injury compared with controls. BM transplantation experiments demonstrated that PAR-1 in nonhematopoietic cells protected mice from CVB3 infection. Transgenic mice overexpressing PAR-1 in cardiomyocytes had reduced CVB3-induced myocarditis. We found that cooperative signaling between PAR-1 and TLR3 in mouse cardiac fibroblasts enhanced activation of p38 and induction of IFN-β and CXCL10 expression. Par1 -/-mice also had decreased CXCL10 expression and increased viral levels in the lung after influenza A infection compared with Par1 +/+ mice. Our results indicate that the tissue factor/thrombin/PAR-1 pathway enhances IFN-β expression and contributes to the innate immune response during single-stranded RNA viral infection.

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