PAR1 biased signaling is required for activated protein C in vivo benefits in sepsis and stroke.

ABSTRACT: Activated protein C (APC) cleaves protease-activated receptor 1 (PAR1) in vitro at R46 to initiate beneficial cell signaling; however, thrombin and APC can cleave at R41. To elucidate PAR1-dependent aspects of the pharmacologic in vivo mechanisms of APC, we generated C57BL/6 mouse strains carrying QQ41 or QQ46 point mutations in PAR1 (F2r gene). Using these strains, we determined whether or not recombinant murine signaling-selective APC mutants would reduce septic death or provide neuroprotection against ischemic stroke when mice carried PAR1-homozygous mutations that prevent cleavage at either R41 or R46. Intercrossing PAR1⁺/R46Q mice generated expected numbers of PAR1^+/+, PAR1⁺/R46Q, and R46Q/R46Q offspring whereas intercrossing PAR1⁺/R4

SUBMITTER: Sinha RK 

PROVIDER: S-EPMC5855020 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature