Highlights
- •Protease-activated receptors (PARs) significantly contribute to the pathogenesis of cardiometabolic diseases.
- •Pharmacological or genetic deletion of the PAR signaling pathway attenuates cardiovascular inflammation and atherogenesis.
- •The PAR signaling pathway may serve as a potential therapeutic target for cardiometabolic disorders.
Abstract
Cardiometabolic disorders, including obesity-related insulin resistance and atherosclerosis,
share sterile chronic inflammation as a major cause; however, the precise underlying
mechanisms of chronic inflammation in cardiometabolic disorders are not fully understood.
Accumulating evidence suggests that several coagulation proteases, including thrombin
and activated factor X (FXa), play an important role not only in the coagulation cascade
but also in the proinflammatory responses through protease-activated receptors (PARs)
in many cell types. Four members of the PAR family have been cloned (PAR 1–4). For
instance, thrombin activates PAR-1, PAR-3, and PAR-4. FXa activates both PAR-1 and
PAR-2, while it has no effect on PAR-3 or PAR-4. Previous studies demonstrated that
PAR-1 and PAR-2 activated by thrombin or FXa promote gene expression of inflammatory
molecules mainly via the NF-κB and ERK1/2 pathways. In obese adipose tissue and atherosclerotic
vascular tissue, various stresses increase the expression of tissue factor and procoagulant
activity. Recent studies indicated that the activation of PARs in adipocytes and vascular
cells by coagulation proteases promotes inflammation in these tissues, which leads
to the development of cardiometabolic diseases. This review briefly summarizes the
role of PARs and coagulation proteases in the pathogenesis of inflammatory diseases
and describes recent findings (including ours) on the potential participation of this
system in the development of cardiometabolic disorders. New insights into PARs may
ensure a better understanding of cardiometabolic disorders and suggest new therapeutic
options for these major health threats.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: October 19, 2022
Accepted:
September 20,
2022
Received:
September 20,
2022
Identification
Copyright
© 2022 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved. All rights reserved.
