Different DOACs Control Inflammation in Cardiac Ischemia-Reperfusion Differently

Area of Science:

• Cardiovascular Research
• Coagulation Cascade Biology
• Inflammation and Immunity

Background:

• Thrombin (fIIa) is central to thrombus formation.
• Other proteases like factor Xa (fXa) and activated protein C (aPC) modulate intracellular signaling via distinct receptors.
• Understanding differential protease inhibition effects is crucial for treating cardiovascular diseases.

Purpose of the Study:

• To investigate the distinct effects of fXa versus fIIa inhibition on gene expression and inflammation in myocardial ischemia-reperfusion injury.
• To elucidate the mechanisms underlying these differential responses.

Main Methods:

• Mice with myocardial ischemia-reperfusion injury were treated with direct fXa inhibitors (fXai) or direct fIIa inhibitors (fIIai).
• Comparable anticoagulant effects were confirmed via ex vivo and in vivo assays.
• Gene expression was analyzed using RNA sequencing; infarct size, aPC generation, and inflammatory markers were quantified.

Main Results:

• Both fXai and fIIai reduced infarct size comparably.
• fXai, but not fIIai, significantly inhibited sterile inflammation by reducing pro-inflammatory cytokines (IL-1β, IL-6, TNFα) and NF-κB/inflammasome activation.
• fXai treatment led to reduced myocardial fibrosis and increased in vivo aPC generation compared to fIIai.

Conclusions:

• Specific inhibition of coagulation proteases yields distinct cellular responses beyond their anticoagulant properties.
• Factor Xa inhibition offers a unique anti-inflammatory benefit in myocardial ischemia-reperfusion injury, mediated partly through activated protein C signaling.
• Targeting specific coagulation proteases may provide tailored therapeutic strategies for cardiovascular conditions.