| Background and Objective:Angiotensin receptor blockers (ARBs) are generally well tolerated and usedextensively in the treatment of hypertension. However, accumulating studies did notshow the superiority of the ARBs in myocardial infarction (MI), instead, someresearches reported that ARBs may increase the morbidity and mortality of MI. As twokinds of RAAS blocker, ARB is not the first choice. Some scholars suggested that thereason is excessive activation of the AT2R. After AT1R blocking, AT2R play a majorrole in upregulation of atherosclerotic inflammatory factor, thus counteract the benefitof AT1R blocking.Argument also exsit whether ARBs have angiogenetic effect besides itsantihypertensive effect. Angiogenensis may play an important role in chronic ischemiccardiovascular diseases. Some researches reported that AT2R might be attributed to thesignaling cascade in the VEGF pathway, thus play an important role in angiogeniceffect.Therefore, in this research, we compared the effects of angiotensin receptor blockerand angiotensin converting enzyme inhibitor on cardiovascular and cerebrovascularmorbidity and mortality in aged patients with hypertension. Meanwhile, we usedirbesartan to stimulate in vitro cultured human umbilical vein endothelial cells(EA.hy926). The present study was aimed at providing clues for elucidating the AT2Rrelated mechanism of angiogenic and inflammatory effects of ARBs through itsbiological effects, gene expression profiling.Methods:We retrospectively reviewed the clinical data of933aged male patients withhypertension who received ARB or ACEI more than2months from January2007to May2011. The primary outcome and the secondary end points were settting to comparecardiovascular and cerebrovascular morbidity and mortality of two kinds of drugs.The human umbilical vein endothelial cell line EA.hy926was grown for24hrs.After treatment with different concentrations of irbesartan. The cell morphology,proliferative capacity, apoptosis and VEGF and SELP gene expression levels werecharacterized. The optimal condition was used to carry out microarray analysis usingAffymetrix U133plus2.0. Quantitative RT-PCR and Western blot analyses were usedto validate differential gene expression related to the angiogenesis and inflammatoryprocess.Design Ang Ⅱ stimulated model of EA.hy926cell line. In order to characterize thechange of NF-κB p65and downstream cytokines and angiogenesis factor in differentcondition, We divided into6groups, the blankgroup, Ang Ⅱ stimulated group, Ang Ⅱstimulated and AT1R blocker group, Ang Ⅱ stimulated and AT2R group, dualblockergroup, Ang Ⅱ stimulatied and NF-κB p65blocker group. We try to elucidate themechanism about the change of the angiogenesis and inflammatory factors afterintervention with irbesartan.Results:Age, drug types, cerebral infarction history, renal dysfunction were the independentpredictors of the primary end points. The risk of the primary end point was higher inARB group than ACEI group. While for the secondary end points, no significantdiference was seen between2groups. Age, coronary heart disease history were theindependent predictors of the secondary end points.Irbesartan promotes cell proliferation. FCM analysis showed no significant changesin cell apoptosis. Cluster analysis and disease classification analysis showed that thetendency of these different genes involved in angiogenesis and inflammation promotethe occurrence and development of atherosclerosis.In Ang Ⅱ stimulated EA.hy926cell model, compared with control group, theexpression of COX2, MMP2, VEGFmRNA and protein increased, especially in Ang Ⅱstimulated group. However, only dual blocker group and NF-κB p65group could decrease the expression of PTGS2, MMP2, VEGFmRNA and protein significantly. Theprotein expression of NF-κBp65is the same.Conclusion:ACEI was more effective than ARB in reducing cardiovascular and cerebrovascularmorbidity and mortality in aged patients with hypertension, when we faced to selectionACEI and ARB, ACEI is preferred.Irbesartan may induce cell proliferation effects and regulate the inflammatory geneexpressions related to atherosclerosis and angiogenetic in EA.hy926cells. There areredundant AT1R and AT2R in EA.hy926cells. Ang Ⅱ exerts biological effectsprimarily through AT1R and AT2R two receptors. The classic NF-κB pathway is thecommon pathway of AT1R and AT2R. Irbesartan regulates inflammatory factors andangiogenetic facrors mainly depend on the activation of NF-κB pathway by AT2R. |
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