A Study And Meta-analysis About The Role Of RAS-inflammation System During The Formation And Development Of Intracranial Aneurysm

In the present study,renin-angiotensin system(RAS)related proteins,including angiotensin ?(Ang ?),angiotensin converting enzyme(ACE)and angiotensin ? type 1 receptor(AT1R)were detected in serum,cerebrospinal fluid and intracranial aneurysm wall tissue samples collected form intracranial aneurysm patients as well as inflammatory factor by enzyme-linked immuno sorbent assay(ELISA)and immunohistochemical method to explore the potential role of RAS during the formation of intracranial aneurysm.What's more,meta-analysis was conducted to assess the correlation between ACE insertion/deletion polymorphisms and ruptured intracranial aneurysm.The results demonstrated that RAS was related with inflammatory in intracranial aneurysm.RAS could promote inflammatory possibly and further lead to the formation of intracranial aneurysms.Meta-analysis showed that the ACE insertion/deletion polymorphism increased the risk of intracranial aneurysms.and the risk was more significant in East Asia than Caucasian.Part1 A study about the role of RAS-inflammation system during the formation of intracranial aneurysmObject:The RAS related proteins and inflammation factors were detected in intracranial aneurysms patients by ELISA,immunohistochemical method and qRT-PCR to explore the potential role of RAS during the formation of intracranial aneurysm.Methods:The admission criteria of experimental group were:1)intracranial aneurysms identified by the CTA or DSA,2)the diameter of intracranial aneurysms was longer than 3mm,3)choose neurosurgical clipping for treatment.The intracranial aneurysm wall tissue samples were collected during the surgery.And the serum samples were collected as well as cerebrospinal fluid samples.Patients with craniocerebral trauma,who chose craniotomy evacuation of hematoma for treatment,were brought into control group.The intracranial aneurysm wall tissue samples were also collected during the surgery.And the cerebrospinal fluid samples were collected as well.Lastly,patients with scalp masses were for serum samples regarded as control group.After collection,the expression of Ang ?,ACE,AT1R,interleukin-6(IL-6),interleukin-1?(IL-1?),tumor necrosis factor-?(TNF-?),endothelial nitric oxide synthase(eNOS),matrix metalloproteinase-9(MMP-9).lipoprotein a(Lp-a)and miRNA-566 were detected separately by ELISA,immunohistochemical method and quantitative real time polymerase chain reaction(qRT-PCR)in those samples.Results:The results of ELISA and immunohistochemical method showed that the expression of Ang ?,ACE,AT1R in serum,cerebrospinal fluid and intracranial aneurysm wall tissue samples collected form intracranial aneurysm patients were significantly increased(p<0.05),except the expression of AT1R in serum samples(p>0.05),when compared to control group.The expression of IL-6,IL-1p,TNF-a in serum samples,and MMP-9 and Lp-a in intracranial aneurysm wall tissue samples were significantly increased(p<0.05),and eNOS was significantly decreased(p<0.05)in intracranial aneurysm patients when compared to control group.The results of qRT-PCR showed that the content of miRNA in intracranial aneurysm wall tissue samples was significantly decreased when compared to control group(p<0.01).What's more,there was a correlation between RAS and inflammation in intracranial aneurysm patients.Conclusions:RAS and inflammation were activated in intracranial aneurysm patients.RAS may act as a proinflammation role,which broke the balance of endothelial cells and smooth muscle cell,degraded extracellular matrix,inhibited the proliferation of endothelial cells and remodeled the cerebrovascular structure,eventually leading to the formation of intracranial aneurysm.Part2 A meta-analysis about ACE polymorphisms with ruptured intracranial aneurysmObject:ACE plays a important role in the regulation of intracranial vascular system.Some reports showed that there may be a correlation between ACE insertion/deletion polymorphisms and intracranial aneurysm.In the present study,we dealt with ACE insertion/deletion polymorphisms and ruptured intracranial aneurysm for a meta-analysis to confirm the correlation.Methods:We searched PubMed,Medline,Web of Science,Wanfang and CNKI for information.Only publications of randomized controlled trials(RCTs)about ruptured intracranial aneurysm and ACE insertion/deletion polymorphisms were selected for analysis.The observing targets included Gene detection method and results.The associations between ACE insertion/deletion polymorphisms and ruptured intracranial aneurysm risk were measured by odds ratios(ORs)with 95%confidence interval(95%CI).?2-based and Q-test were used to verify heterogeneity assumption,and quantifed by the I2 value.If heterogeneity was lacked in the studies(Ph>0.1 and I2<50%),the overall ORs value would be calculated by the fxed-effects model.Otherwise,the random-effects model was used.Results:Of the 80 studies identified in the search,6 RCTs involving 2387 patients met the inclusion criterias.The results of meta-analysis showed the ACE insertion/deletion polymorphisms were associated with an increased risk of ruptured intracranial aneurysm in the allele mode l(I vs.D,OR=1.26,95%CI=1.10-1.44,POR=0.001),homozygote comparison of codominant(II vs.DD,OR=1.60,95%CI=1.26-2.03,POR=0.00),and dominant model((?+ID)vs.DD,OR=1.32,95%CI=1.00-1.73,POR=0.047).In the subgroup analysis for ethnicity,the ACE insertion/deletion polymorphisms showed a significant contribution to the risk of ruptured intracranial aneurysm in East Asian in homozygote comparison of codominant(? vs.DD,OR=2.04,95%CI=1.12-3.70,POR=0.02)and dominant model((?+ID)vs.DD,OR=1.93,95%CI=1.32-2.80,POR=0.001),which showed no difference in the Caucasian population.In addition,in the subgroup analysis for the hospital-based group,the study showed a significantly increased risk in all genetic models except for in the recessive model(? vs.(ID+DD),OR=1.12,95%CI=0.73-1.74,POR=0.602).Similar fndings were revealed in the allele model(? vs.D,OR=1.28,95%CI=1.08-1.52,POR=0.005)and homozygote comparison of codominant model(? vs.DD,OR=1.56,95%CI=1.12-2.17,POR=0.009)in the population-based subgroup.Conclusions:The ACE polymorphisms are associated with an increased risk of ruptured intracranial aneurysm,particularly in Asian individuals.