Background and Aims:Hepatic ischemia-reperfusion injury(HIRI)is a prevalent complication of liver transplantation,partial hepatectomy,and severe infection,necessitating the development of more effective clinical strat...Background and Aims:Hepatic ischemia-reperfusion injury(HIRI)is a prevalent complication of liver transplantation,partial hepatectomy,and severe infection,necessitating the development of more effective clinical strategies.Receptor activity–modifying protein 1(RAMP1),a member of the G protein–coupled receptor adapter family,has been implicated in numerous physiological and pathological processes.The study aimed to investigate the pathogenesis of RAMP1 in HIRI.Methods:We established a 70%liver ischemia-reperfusion model in RAMP1 knockout(KO)and wild-type mice.Liver and blood samples were collected after 0,6,and 24 h of hypoxia/reperfusion.Liver histological and serological analyses were performed to evaluate liver damage.We also conducted in-vitro and in-vivo experiments to explore the molecular mechanism underlying RAMP1 function.Results:Liver injury was exacerbated in RAMP1-KO mice compared with the sham group,as evidenced by increased cell death and elevated serum transaminase and inflammation levels.HIRI was promoted in RAMP1-KO mice via the induction of hepatocyte apoptosis and inhibition of proliferation.The absence of RAMP1 led to increased activation of the extracellular signal–regulated kinase(ERK)/mitogen-activated protein kinase(MAPK)pathway and yes-associated protein(YAP)phosphorylation,ultimately promoting apoptosis.SCH772984,an ERK/MAPK phosphorylation inhibitor,and PY-60,a YAP phosphorylation inhibitor,reduced apoptosis in in-vitro and in-vivo experiments.Conclusions:Our findings suggest that RAMP1 protects against HIRI by inhibiting ERK and YAP phosphorylation signal transduction,highlighting its potential as a therapeutic target for HIRI and providing a new avenue for intervention.展开更多
基金supported by:The National Natural Science Foundation of China(82270688,81402426)The Natural Science Foundation.of Guangdong Province(2021A1515010726,2022A1515012650,2020A1515010302)+1 种基金The Cultivation Project of National Natural Science Foundationof the Third Affliated Hospital of Sun Yat-sen University(No.2020GzRPYMS09)Science and Technology ProjectsinGuangzhou(No.202102010310,202201020427).
文摘Background and Aims:Hepatic ischemia-reperfusion injury(HIRI)is a prevalent complication of liver transplantation,partial hepatectomy,and severe infection,necessitating the development of more effective clinical strategies.Receptor activity–modifying protein 1(RAMP1),a member of the G protein–coupled receptor adapter family,has been implicated in numerous physiological and pathological processes.The study aimed to investigate the pathogenesis of RAMP1 in HIRI.Methods:We established a 70%liver ischemia-reperfusion model in RAMP1 knockout(KO)and wild-type mice.Liver and blood samples were collected after 0,6,and 24 h of hypoxia/reperfusion.Liver histological and serological analyses were performed to evaluate liver damage.We also conducted in-vitro and in-vivo experiments to explore the molecular mechanism underlying RAMP1 function.Results:Liver injury was exacerbated in RAMP1-KO mice compared with the sham group,as evidenced by increased cell death and elevated serum transaminase and inflammation levels.HIRI was promoted in RAMP1-KO mice via the induction of hepatocyte apoptosis and inhibition of proliferation.The absence of RAMP1 led to increased activation of the extracellular signal–regulated kinase(ERK)/mitogen-activated protein kinase(MAPK)pathway and yes-associated protein(YAP)phosphorylation,ultimately promoting apoptosis.SCH772984,an ERK/MAPK phosphorylation inhibitor,and PY-60,a YAP phosphorylation inhibitor,reduced apoptosis in in-vitro and in-vivo experiments.Conclusions:Our findings suggest that RAMP1 protects against HIRI by inhibiting ERK and YAP phosphorylation signal transduction,highlighting its potential as a therapeutic target for HIRI and providing a new avenue for intervention.
