Effects Of Estrogen On The Tissue Injury And Renin Aniotensis System In Mice Following Hemorrhagic Shock

Hemorrhagic shock caused by traumatic hemorrhage,esophageal varices rupture,and peptic ulcer is a common emergency in clinical practice.Hypovolemic can lead the blood pressure decreasing,tissues perfusion reducing,and increased anaerobic metabolism,in turn lead to increasing the level of lactic acid and metabolic acidosis occur,at the end result to multiple organ failure.Renin angiotensin system(RAS)is an important humoral regulation system in the body.The RAS has two key axes,angiotensin-converting enzyme(ACE)-angiotensin II(Ang II)– Ang II 1 recepter(AT1R)and ACE2-Ang(1-7)-Mas receptor(MasR).These two axes are involved in the balance of RAS.Previous studies showed that hemorrhagic shock could up-regulate the expression of ACE-AngII-AT1 R axis and down-regulate the expression of ACE2-Ang(1-7)-MasR axis.The main component of estrogen is estradiol,which belongs to G18 steroid hormone.Oestrogen is mainly secreted from the ovaries.Studies showed that estrogen can improve renal and lung injury following hemorrhagic shock,but its mechanisem need further investigate.In this study,we used 17?-estradiol(E2)as an intervention factor,and observe the effect of estrogen on RAS content of myocardial tissue in mice following hemorrhagic shock.Thirty-six C57 female mice were randomly divided into ovariectomy group(OVX group;n=24 ovariectomy)and sham ovariectomy group(OVI group;n=12 only removed a small amount of adipose tissue around the ovary).A week later,the mice in the OVX group were divided into 2 groups,one group treat with E2(140 ?g/kg.d)through subcutaneous administration of neck,another group was treated with the same amount of vehicle.The OVI group was treated with the same amount of vehicle.These treatment were sustained a week.Then,the experimental group was OVX+E2 group,OVX+Vehicle group and OVI+Vehicle group.A week later,the hemorrhagic shock model was established,and the mice in the 3 groups were divided into hemorrhagic shock group(Shock group)and sham group(Sham group).After the preparation of hemorrhagic shock model,collected myocardium,renel,lung tissues and the whole blood sample.We assessed the degree of myocardium injury by detecting LDH-1,CK-MB,IMA,Hcy,and assessed the renal function by detecting the Urea,Cre.HE staining method was used to observe the injury of tissue structure.The expressions of ACE,ACE2,MasR,AT1 R were detected by RT-PCR method.The contents of estrogen,Ang II and Ang(1-7)were detected by using ELISA.Results showed that OVX decreased the E2 concentration in plasma of female mice,which was reversed by E2 treatment.And this result determined the operation was successful.Analysis of biomarkers in myocardium injury indicated that OVX induced an increasing CK-MB level,which was reversed by E2 treatment.OVX treatment induced disorganized myocardial fibers,and aggravated the myocardium injury in female mice following hemorrhagic shock,which was reversed by E2 treatment.Hemorrhagic shock induced increase in the expression of ACE mRNA,decreasing ACE2 mRNA expression,increasing the AngII level,and then increased the ratio of ACE/ACE2 and Ang II/Ang(1-7),and also increased the mRNA expression of AT1 R in myocardial,E2 treatment decreased the level of ACE,AT1 R mRNA and Ang II in OVX group mice,and then decreased the ratio of ACE/ACE2,Ang II/Ang(1-7),AT1R/Mas1 R.Hemorrhagic shock induced increasing the level of Urea and renel histology injury in the OVI and OVX groups;E2 treatment decreased the Urea level and alleviated the histology injury.Hemorrhagic shock have not induced the changes of ACE,ACE2,ACE/ACE2,Ang II,Ang(1-7),Ang II/ Ang(1-7)?AT1R?Mas1R?AT1R/Mas1 R significantly in OVI or OVX group mice;E2 treatment only increased the Ang(1-7)level in OVX group and the expression of Mas1 R after OVX sham operation.Hemorrhagic shock induced the lung histology injury,which was alleviated by E2 treatment.Hemorrhagic shock did not induce the changes of ACE,ACE2,ACE/ACE2,AT1 R,Mas1R,AT1R/Mas1 R significantly in the OVI or OVX groups and the change of Ang?,Ang(1-7),Ang?/ Ang(1-7)significantly in OVI group,but hemorrhagic shock induced the increasing of Ang?,Ang?/ Ang(1-7)and the decreasing of Ang(1-7)significantly following OVX,and the level of Ang?,Ang?/ Ang(1-7)were higher than OVI+Shock group;E2 treatment decreased the level of Ang ?,Ang ? /Ang(1-7)and the expression of Mas1 R after OVX following Hemorrhagic shock,and increased the expression of Mas1 R after OVX following sham operation,and had no significantly effect on the ACE,ACE2,ACE/ACE2,Ang(1-7),AT1 R,AT1R/Mas1 R after OVX following hemorrhagic shock.These results showed that estrogen treatment attenuating the degree of myocardial,renel,lung tissue injury following hemorrhagic shock,and the mechanism by wich E2 alleviating the injury of myocardial was related to RAS,but the mechanism of alleviating the injury of renel and lung may be related to RAS,and the related mechanism need to be further investigated.