Novel anti-thrombotic mechanisms mediated by mas receptor as result of balanced activities between the kallikrein/kinin and the renin-angiotensin systems
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Resumo
The risk of thrombosis, a globally growing challenge and a major cause of death, is influenced by
various factors in the intravascular coagulation, vessel wall, and cellular systems. Among the
contributors to thrombosis, the contact activation system and the kallikrein/kinin system, two
overlapping plasma proteolytic systems that are often considered as synonymous, regulate
thrombosis from different aspects. On one hand, components of the contact activation system
such as factor XII initiates activation of the coagulation proteins promoting thrombus formation on
artificial surfaces through factor XI- and possibly prekallikrein-mediated intrinsic coagulation. On
the other hand, physiological activation of plasma prekallikrein in the kallikrein/kinin system on
endothelial cells liberates bradykinin from associated high-molecular-weight kininogen to
stimulate the constitutive bradykinin B2 receptor to generate nitric oxide and prostacyclin to
induce vasodilation and counterbalance angiotensin II signaling from the renin-angiotensin system which stimulates vasoconstriction. In addition to vascular tone regulation, this interaction
between the kallikrein/kinin and renin-angiotensin systems has a thrombo-regulatory role
independent of the contact pathway. At the level of the G-protein coupled receptors of these
systems, defective bradykinin signaling due to attenuated bradykinin formation and/or decreased
B2 receptor expression, as seen in murine prekallikrein and B2 receptor null mice, respectively,
leads to compensatory overexpressed Mas, the receptor for angiotensin-(1-7) of the reninangiotensin system. Mas stimulation and/or its increased expression contributes to maintaining a
healthy vascular homeostasis by generating graded elevation of plasma prostacyclin which
reduces thrombosis through two independent pathways: (1) increasing the vasoprotective
transcription factor Sirtuin 1 to suppress tissue factor expression, and (2) inhibiting platelet
activation. This review will summarize the recent advances in this field that support these
understandings. Appreciating these subtle mechanisms help to develop novel anti-thrombotic
strategies by targeting the vascular receptors in the renin-angiotensin and the kallikrein/kinin
systems to maintain healthy vascular homeostasis
Palabras clave
The contact activation system; The kallikrein/kinin system; The renin-angiotensin system; Mas; Prostacyclin; SIRT1Link para o recurso
https://doi.org/10.1016/j.phrs.2020.105096Collections
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