Objective To examine the effects of exogenously administered intermedin （IMD,adrenomedullin-2） on arterial blood pressure,cardiac function and the cardiovascular IMD receptor system in spontaneously hypertensive ra...Objective To examine the effects of exogenously administered intermedin （IMD,adrenomedullin-2） on arterial blood pressure,cardiac function and the cardiovascular IMD receptor system in spontaneously hypertensive rats （SHRs） as well as to investigate the associated mechanisms.Methods Thirteen week-old male rats were divided in Wistar Kyoto （WKY） group （n =12）,SHR group （n =12）,IMD group （SHRs infused with IMD 1-47 500 ng/kg per hour,n =12）,and ADM group （SHRs infused with adrenomedullin 500 ng/kg per hour,n =12）.Results A two-week continuous administration of low dose IMD 1-47 via mini-osmotic pumps markedly reduced blood pressure,the maximal rates of increase and decrease of left-ventricle pressure development （LV ± dp/dtmax）,left ventricular systolic pressure and heart rate in SHRs.Furthermore,IMD also inhibited protein over-expression of cardiovascular IMD receptors,myocardial Receptor Activity-Modifying Proteins （RAMP1 and RAMP2）,aortic RAMP1,RAMP2,RAMP3,and calcitonin receptor-like receptor （CRLR）;suppressed up-regulation of aortic RAMP1,RAMP2,RAMP3 and CRLR gene expression; and markedly elevated the mRNA abundance of myocardial atrial natriuretic peptide （ANP） and myocardial brain natriuretic peptide （BNP）.Additionally,IMD 1-47 administration in SHRs increased aortic cAMP concentration and reduced myocardial cAMP concentration.Conclusion These findings support the speculation that IMD,as a cardiovascular active peptide,is involved in blood pressure reduction and cardiac function amelioration during hypertension.The mechanism underlying this effect may involve IMD binding of a receptor complex formed by RAMPs and CRLR,and consequential regulation of cAMP levels and other cardiovascular active factors,such as ANP and BNP.展开更多
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
文摘Objective To examine the effects of exogenously administered intermedin （IMD,adrenomedullin-2） on arterial blood pressure,cardiac function and the cardiovascular IMD receptor system in spontaneously hypertensive rats （SHRs） as well as to investigate the associated mechanisms.Methods Thirteen week-old male rats were divided in Wistar Kyoto （WKY） group （n =12）,SHR group （n =12）,IMD group （SHRs infused with IMD 1-47 500 ng/kg per hour,n =12）,and ADM group （SHRs infused with adrenomedullin 500 ng/kg per hour,n =12）.Results A two-week continuous administration of low dose IMD 1-47 via mini-osmotic pumps markedly reduced blood pressure,the maximal rates of increase and decrease of left-ventricle pressure development （LV ± dp/dtmax）,left ventricular systolic pressure and heart rate in SHRs.Furthermore,IMD also inhibited protein over-expression of cardiovascular IMD receptors,myocardial Receptor Activity-Modifying Proteins （RAMP1 and RAMP2）,aortic RAMP1,RAMP2,RAMP3,and calcitonin receptor-like receptor （CRLR）;suppressed up-regulation of aortic RAMP1,RAMP2,RAMP3 and CRLR gene expression; and markedly elevated the mRNA abundance of myocardial atrial natriuretic peptide （ANP） and myocardial brain natriuretic peptide （BNP）.Additionally,IMD 1-47 administration in SHRs increased aortic cAMP concentration and reduced myocardial cAMP concentration.Conclusion These findings support the speculation that IMD,as a cardiovascular active peptide,is involved in blood pressure reduction and cardiac function amelioration during hypertension.The mechanism underlying this effect may involve IMD binding of a receptor complex formed by RAMPs and CRLR,and consequential regulation of cAMP levels and other cardiovascular active factors,such as ANP and BNP.
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.
