原發(fā)性高血壓病患者血清瘦素、可溶性瘦素受體及沉默信息調(diào)節(jié)因子相關(guān)酶3水平與動脈粥樣硬化的關(guān)系研究

胡迪聃，徐彤彤，王文艷，顧婉紅

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·論著·

原發(fā)性高血壓病患者血清瘦素、可溶性瘦素受體及沉默信息調(diào)節(jié)因子相關(guān)酶3水平與動脈粥樣硬化的關(guān)系研究

胡迪聃，徐彤彤，王文艷，顧婉紅

目的探討原發(fā)性高血壓病(EH)患者血清瘦素(LP)、可溶性瘦素受體(SLR)及沉默信息調(diào)節(jié)因子相關(guān)酶3(SIRT3)水平與動脈粥樣硬化(AS)之間的關(guān)系。方法選取2015年7月—2016年1月在桂林醫(yī)學院附屬醫(yī)院心血管內(nèi)科及特需病區(qū)住院的EH患者60例為EH組，及同期在本院進行體檢的健康成年人60例為對照組。根據(jù)高血壓分級將EH組患者分為高血壓1、2、3級，各20例。根據(jù)頸動脈內(nèi)膜-中層厚度(cIMT)將所有受試者分為cIMT正常組55例、cIMT增厚組52例和頸動脈斑塊形成組13例。采用ELISA檢測所有受試者血清LP、SLR及SIRT3水平，以cIMT來評估AS程度，同時檢測空腹血糖(FPG)、總膽固醇(TC)、三酰甘油(TG)、高密度脂蛋白膽固醇(HDL-C)、低密度脂蛋白膽固醇(LDL-C)、尿素氮(BUN)、肌酐(Cr)等相關(guān)指標。結(jié)果EH組患者血清LP、SIRT3水平及cIMT均高于對照組，血清SLR水平低于對照組，差異有統(tǒng)計學意義(P<0.05)。不同高血壓分級患者血清LP、SLR、SIRT3水平及cIMT間差異均有統(tǒng)計學意義(P<0.05)，其中高血壓3級患者血清LP、SIRT3水平及cIMT高于高血壓1、2級患者，血清SLR水平低于高血壓1、2級患者；高血壓2級患者血清LP、SIRT3水平高于高血壓1級患者，血清SLR水平低于高血壓1級患者。不同cIMT分組患者血清LP、SLR、SIRT3水平間差異均有統(tǒng)計學意義(P<0.05)，其中頸動脈斑塊形成組患者血清LP、SIRT3水平高于cIMT正常組、增厚組，血清SLR水平低于cIMT正常組、增厚組；cIMT增厚組患者血清LP、SIRT3水平高于cIMT正常組，血清SLR水平低于cIMT正常組。cIMT與LP、SIRT3呈直線正相關(guān)(r值分別為0.725、0.683，P<0.05)，與SLR呈直線負相關(guān)(r=-0.720，P<0.05)。多元Logistic回歸分析結(jié)果顯示，LP、SIRT3是cIMT增厚的獨立危險因素(P<0.05)，而SLR是cIMT增厚的獨立保護因素(P<0.05)。結(jié)論血清LP、SLR、SIRT3水平與高血壓及cIMT密切相關(guān)，說明瘦素抵抗、SIRT3可能參與了EH及AS的形成和發(fā)展。

瘦素；受體,瘦素；沉默信息調(diào)節(jié)因子相關(guān)酶3；高血壓；動脈粥樣硬化

胡迪聃，徐彤彤，王文艷，等.原發(fā)性高血壓病患者血清瘦素、可溶性瘦素受體及沉默信息調(diào)節(jié)因子相關(guān)酶3水平與動脈粥樣硬化的關(guān)系研究[J].中國全科醫(yī)學，2016，19(22)：2676-2680.[www.chinagp.net]

HU D D,XU T T,WANG W Y,et al.Correlation between serum leptin,soluble leptin receptor as well as silent information regulator related enzyme 3 levels and atherosclerosis in patients with essential hypertension[J].Chinese General Practice，2016，19(22)：2676-2680.

原發(fā)性高血壓病(essential hypertension,EH)是最常見的由多種因素導致的持續(xù)進展狀態(tài)的心血管疾病，長期高血壓可引起心臟結(jié)構(gòu)和功能的改變，導致嚴重的心血管并發(fā)癥，是增加血管病變、動脈粥樣硬化(atherosclerosis,AS)的主要危險因素。當AS發(fā)展到一定程度，尤其是有明顯血管狹窄或閉塞，并引起相應器官病變時，診斷并不困難，但早期診斷并不容易。目前可通過頸動脈超聲技術(shù)檢測頸動脈內(nèi)膜-中層厚度(carotid intima media thickness,cIMT)及斑塊形成，以cIMT作為早期評估AS病變程度的指標[1]。高血壓所致的AS是由血管內(nèi)皮損傷導致的慢性炎性反應，同時神經(jīng)體液因素也是重要機制之一。本研究通過探討EH患者血清瘦素(leptin,LP)、可溶性瘦素受體(soluble leptin receptor,SLR)及沉默信息調(diào)節(jié)因子相關(guān)酶3(silent information regulator factor related enzyme 3,SIRT3)水平與cIMT的相關(guān)性，為評估和防治AS提供有益線索。

1　資料與方法

1.2方法

1.2.1血壓測量待測者坐位安靜休息至少10 min后，選擇經(jīng)校準的臺式水銀柱血壓計連續(xù)測量右上肢肱動脈血壓2次，每次至少間隔1～2 min，取平均值，分別以Korotkof第1音和第5音確定收縮壓(systolic blood pressure,SBP)和舒張壓(diastolic blood pressure,DBP)水平。若2次測量的SBP或DBP讀數(shù)相差≥5 mm Hg(1 mm Hg=0.133 kPa)，則相隔5 min后再測量，取3次測量的平均值并記錄，作為被測者的血壓值。

1.2.2血清LP、SLR及SIRT3水平檢測所有受試者禁食12 h以上，于次日清晨空腹抽取肘靜脈血2 ml，離心半徑13 cm，3 000 r/min離心10 min后，分離上層清夜置-70 ℃冰箱中保存待測。血清LP、SLR及SIRT3水平均采用ELISA測定，試劑盒購自上海一基實業(yè)有限公司，按說明書具體步驟操作，測定吸光度，由標準曲線計算血清LP、SLR及SIRT3水平。

1.2.3相關(guān)指標檢測應用7600型全自動生化分析儀測定空腹血糖(fasting plasma glucose,FPG)、總膽固醇(total cholesterol,TC)、三酰甘油(triacylglycerol,TG)、高密度脂蛋白膽固醇(high density lipoprotein cholesterol,HDL-C)、低密度脂蛋白膽固醇(low density lipoprotein cholesterol,LDL-C)、尿素氮(blood urea nitrogen,BUN)、肌酐(creatinine,Cr)、尿酸(uric acid,UA)、同型半胱氨酸(homocysteine,Hcy)及超敏C反應蛋白(high sensitivity C reactive protein,hs-CRP)水平。測身高、體質(zhì)量、腰圍、臀圍，計算BMI、腰臀比(waist-to-hip ratio,WHR)；腰臀比=腰圍(cm)/臀圍(cm)。

1.2.4頸動脈多普勒彩超檢查及分組使用德國西門子Acuson Sequoia 512型多普勒彩超診斷儀，由本院超聲科同一資深專業(yè)醫(yī)師操作，采用7.5～10 MHz探頭。檢查對象取去枕仰臥位，頭偏向檢查側(cè)對側(cè)，充分暴露頸部，分別探查雙側(cè)頸總動脈、頸動脈分叉及雙側(cè)頸內(nèi)、外動脈。為觀察血清LP、SLR及SIRT3水平與cIMT的關(guān)系，根據(jù)血管超聲檢查指南中cIMT分組標準，將所有患者分為cIMT正常組55例(cIMT<1.0 mm)、cIMT增厚組52例(cIMT≥1.0 mm) 和頸動脈斑塊形成組13例(局限性cIMT≥1.5 mm)[3]。對照組中47例進入cIMT正常組，13例進入cIMT增厚組；EH組中8例進入cIMT正常組，39例進入cIMT增厚組，13例進入斑塊形成組。

2　結(jié)果

2.1兩組患者觀察指標比較兩組患者BMI、WHR、FPG、TC、TG、LDL-C、BUN、Cr間差異無統(tǒng)計學意義(P>0.05)；而SBP、DBP、LP、SLR、SIRT3、cIMT、HDL-C、UA、Hcy、hs-CRP間差異有統(tǒng)計學意義(P<0.05，見表1) 。

表1　兩組患者觀察指標比較±s)

注：EH=原發(fā)性高血壓病，WHR=腰臀比，SBP=收縮壓，DBP=舒張壓，LP=瘦素，SLR=可溶性瘦素受體，SIRT3=沉默信息調(diào)節(jié)因子相關(guān)酶3，cIMT=頸動脈內(nèi)膜-中層厚度，F(xiàn)PG=空腹血糖，TC=總膽固醇，TG=三酰甘油，HDL-C=高密度脂蛋白膽固醇，LDL-C=低密度脂蛋白膽固醇，BUN=尿素氮，Cr=肌酐，UA=尿酸，Hcy=同型半胱氨酸,hs-CRP=超敏C反應蛋白；1 mm Hg=0.133 kPa

2.2不同高血壓分級患者血清LP、SLR、SIRT3水平及cIMT比較不同高血壓分級患者血清LP、SLR、SIRT3水平及cIMT間差異均有統(tǒng)計學意義(P<0.05)，其中高血壓3級患者血清LP、SLR、SIRT3水平及cIMT與高血壓1、2級患者比較，高血壓2級患者血清LP、SLR、SIRT3水平及cIMT與高血壓1級患者比較，差異均有統(tǒng)計學意義(P<0.05，見表2)。

表2　不同高血壓分級患者血清LP、SLR、SIRT3水平及cIMT比較

注：與高血壓1級比較，aP<0.05；與高血壓2級比較，bP<0.05

2.3不同cIMT分組患者血清LP、SLR、SIRT3水平比較不同cIMT分組患者血清LP、SLR、SIRT3水平間差異均有統(tǒng)計學意義(P<0.05)。其中頸動脈斑塊形成組患者血清LP、SLR、SIRT3水平與cIMT正常組、增厚組比較，cIMT增厚組患者血清LP、SLR、SIRT3水平與cIMT正常組比較，差異均有統(tǒng)計學意義(P<0.05，見表3)。

表3　不同cIMT分組患者血清LP、SLR、SIRT3水平比較

注：與cIMT正常組比較，aP<0.05；與cIMT增厚組比較，bP<0.05

2.4cIMT與其他觀察指標的相關(guān)性分析cIMT與BMI、WHR、FPG、TC、TG、LDL-C、BUN、Cr無直線相關(guān)關(guān)系(r值分別為0.113、0.043、0.108、0.178、0.178、0.138、0.117、0.075，P>0.05)；而與SBP、DBP、LP、SIRT3、HDL-C、UA、Hcy、hs-CRP呈直線正相關(guān)(r值分別為0.636、0.581、0.725、0.683、0.196、0.181、0.334、0.226，P<0.05)，與SLR呈直線負相關(guān)(r=-0.720，P<0.05)。

2.5cIMT影響因素的多元Logistic回歸分析以cIMT有無增厚為因變量(賦值：cIMT正常組=0，cIMT增厚組及頸動脈斑塊形成組=1)，以SBP、DBP、LP、SLR、SIRT3、HDL-C、UA、Hcy、hs-CRP為自變量，進行多元Logistic回歸分析。結(jié)果顯示，LP、SIRT3是cIMT增厚的獨立危險因素(P<0.05)，而SLR、Hcy是cIMT增厚的獨立保護因素(P<0.05，見表4)。

表4　cIMT影響因素的多元Logistic回歸分析

3　討論

LP是一種主要由脂肪組織分泌的蛋白質(zhì)類激素，主要通過與其受體結(jié)合而產(chǎn)生生物學效應，其與許多心血管疾病的發(fā)生、發(fā)展密切相關(guān)[4]。在體內(nèi)，LP過度表達可反饋下調(diào)SLR的產(chǎn)生；而LP信號缺陷導致SLR增加，上調(diào)LP水平。由于LP和SLR之間反饋調(diào)節(jié)機制的存在，SLR可作為檢測LP生物學活性的重要指標。本研究顯示EH組血清LP水平明顯高于對照組，血清SLR水平明顯低于對照組，且隨著高血壓分級增高，血清LP水平升高，血清SLR水平下降，說明EH患者存在瘦素抵抗(leptin resistence,LR)現(xiàn)象，且與高血壓分級密切相關(guān)。已有相關(guān)研究認為LR與高血壓存在關(guān)聯(lián)性[5]。其引起高血壓的原因可能為：(1)高LP血癥可引起交感神經(jīng)系統(tǒng)(sympathetic nervous system,SNS)激活、外周血管收縮及促進腎小管對水、鈉的重吸收，導致水鈉潴留，致使血壓升高[6]；(2)血清LP水平與腎素活性及醛固酮水平相關(guān)，提示LP可能介導腎素-血管緊張素-醛固酮系統(tǒng)(renin angiotensin aldosterone system,RAAS)的激活使血壓升高[7]；(3)同時，血清LP水平升高，其與受體結(jié)合增加，可增強二磷酸腺苷(adenosine diphosphate,ADP)誘導的血小板聚集，引起外周血管收縮，增加外周阻力[8]。由此說明，高血壓患者存在LP及LP受體異常，其可通過復雜機制影響EH的進程。

除此之外，LP在AS形成中扮演著重要角色[4]。AS是一種慢性炎性反應，而LP的分泌異常誘導機體產(chǎn)生各種炎性因子參與炎性反應，從而加速AS進程[9-10]。SCHAFER等[8]發(fā)現(xiàn)LP可調(diào)節(jié)血小板功能，促進血小板的黏附、聚集、活化等過程，增加動靜脈血栓的形成。CIRILLO等[11]認為LP能增加細胞黏附分子(cell adhesion molecule,CAM)和組織因子的表達，促進凝血反應。王先梅等[12]研究發(fā)現(xiàn)EH患者血清LP水平明顯升高，且與cIMT存在相關(guān)性。本研究結(jié)果顯示，血清LP水平隨cIMT增厚而增高，而血清SLR水平隨cIMT增厚而降低；cIMT與LP呈直線正相關(guān)，與SLR呈直線負相關(guān)；LP是cIMT增厚的獨立危險因素，而SLR會降低cIMT增厚的危險性。以上說明LR與AS密切相關(guān)，并影響AS的進程。

SIRT3是一類煙酰胺腺嘌呤二核苷酸(nicotinamide adenine dinucleotide,NAD+)依賴性組蛋白去乙酰化酶，在體內(nèi)分布廣泛，與多種心血管疾病，尤其是早期AS形成密切相關(guān)，且對心血管系統(tǒng)具有重要保護作用[13]。本研究結(jié)果顯示，EH組血清SIRT3水平明顯高于對照組，且隨高血壓分級增加，血清SIRT3水平升高。故推測在高血壓或交感神經(jīng)興奮等應激狀態(tài)下，心肌細胞代償性SIRT3表達增加以減輕血流動力學超負荷對機體造成的損傷，從而影響EH的發(fā)生發(fā)展[14]。研究發(fā)現(xiàn)，血管平滑肌細胞中SIRT3隨著血管緊張素Ⅱ(Angiotensin Ⅱ,Ang Ⅱ)水平升高而表達增加，抑制由Ang Ⅱ誘導血管平滑肌細胞增殖；而敲除SIRT3基因后，血管平滑肌細胞增殖加快，可誘發(fā)AS的發(fā)生發(fā)展[14]。同時，體內(nèi)活性氧(reactive oxygen species,ROS)的過度累積與AS發(fā)病相關(guān)，而SIRT3可直接或間接下調(diào)ROS水平，促進內(nèi)皮型一氧化氮合酶(endothelial nitric oxide synthase,eNOS)生成，以改善血管內(nèi)皮功能[15-16]。BELL等[17]認為線粒體SIRT3可通過直接去乙?；せ铄i超氧化物歧化酶(manganese superoxide dismutase,MnSOD)及異檸檬酸脫氫酶2(isocitrate dehydrogenase 2,IDH2)等抗氧化因子，啟動抗氧化過程降低ROS的蓄積，延緩AS進程。本研究結(jié)果顯示，血清SIRT3水平隨cIMT增厚而增高；cIMT與SIRT3呈直線正相關(guān)；SIRT3是cIMT增厚的獨立危險因素，說明SIRT3與AS密切相關(guān)，對評估AS程度具有一定意義。

綜上所述，LR、SIRT3與cIMT密切相關(guān)，可能參與了EH及AS的形成和發(fā)展，但具體作用機制尚不明確，有待于進一步深入研究。本研究結(jié)果提示，血清LP、SLR及SIRT3水平的變化可作為評估EH及AS病情和嚴重程度的早期預測指標，為EH及AS的診療提供新思路，具有一定的臨床參考價值。

作者貢獻：胡迪聃、徐彤彤負責試驗設(shè)計與實施、撰寫論文、成文并對文章負責；王文艷負責試驗實施、評估、資料收集；顧婉紅負責質(zhì)量控制與審校。

本文無利益沖突。

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(本文編輯：崔沙沙)

Correlation Between Serum Leptin,Soluble Leptin Receptor as Well as Silent Information Regulator Related Enzyme 3 Levels and Atherosclerosis in Patients With Essential Hypertension

HUDi-dan,XUTong-tong,WANGWen-yan,GUWan-hong.VIPWard,AffiliatedHospitalofGuilinMedicalUniversity,Guilin541001,China

Correspondingauthor:XUTong-tong,VIPWard,AffiliatedHospitalofGuilinMedicalUniversity,Guilin541001,China;E-mail：xutongtongguilin@163.com

ObjectiveTo analyze the relationship between serum leptin(LP),soluble leptin receptor(SLR) and silent information regulator factor related enzyme 3(SIRT3) with atherosclerosis(AS)in patients with essential hypertension (EH).Methods60 cases with EH,who were hospitalized in Cardiovascular Department of Internal Medicine and VIP Ward of the Affiliated Hospital of Guilin Medical College from July 2015 to January 2016,were selected as the EH group,and 60 cases of healthy adults examined medically during the corresponding period in our hospital were selected as the control group.The 60 cases with EH were divided into the patients with hypertension stage 1,stage 2 and stage 3 according the hypertension grading,with each stage 20 cases respectively.All subjects were divided in accordance with carotid intima media thickness (cIMT) into cIMT normal group with 55 cases,cIMT thickness group with 52 cases and the plaque formation group with 13 cases.Serum LP,SLR and SIRT3 levels were tested by ELISA method,and cIMT was used to measure the degrees of AS and to examine the relative indicators of fasting plasma glucose(FPG),total cholesterol(TC),triacylglycerol(TG),high density lipoprotein cholesterol(HDL-C),low density lipoprotein cholesterol(LDL-C),blood urea nitrogen(BUN) and creatinine(Cr),etc.ResultsThe cIMT and serum LP,SIRT3 levels of EH group were significantly higher than those of the control group,while serum SLR level of the EH group was significantly lower than that of control group,and differences were statistically significant (P<0.05).Differences among cIMT and serum LP,SIRT3 levels of the patients with different hypertension grades were statistically significant (P<0.05).Among them,cIMT and serum LP,SIRT3 levels of the patients with hypertension stage 3 were significantly higher than that of patients with hypertension stage 1 and 2,while serum SLR level was lower than that of patients with hypertension stage 1 and 2;cIMT and serum LP,SIRT3 levels of the patients with hypertension stage 2 were significantly higher than those of patients with hypertension stage 1,while serum SLR level was lower than that of patients with hypertension 1.Differences among serum LP,SIRT3 levels of patients in different cIMT groups were statistically significant (P<0.05),in which serum LP,SIRT3 levels of patients in the plaque formation group were higher than those of patients in cIMT thickness group as well as the normal group,while serum SLR level was lower than that of patients in cIMT thickness group as well as the normal group,serum LP,SIRT3 levels of cIMT thickness group were higher than those of patients in the normal group,while serum SLR level of patients in the former group was lower than that of patients in the latter group.The cIMT level was linearly positive correlated with serum LP and SIRT3 levels(rvalues were 0.725,0.683,P<0.05) and linearly negative correlated with serum SLR level(rvalue was -0.720,P<0.05).Multivariate Logistic regression analysis showed that SIRT3 and LP were independent risk factors for CIMT thickening (P<0.05),while SLR was an independent protective factor for CIMT thickening (P<0.05).ConclusionSerum LP,SLR and SIRT3 levels are closely associated with hypertension and cIMT,which indicates the possible participation of LP resistance and SIRT3 in the development and progression of EH and AS.

Leptin;Receptors,leptin;Silent information regulator factor related enzyme 3;Hypertension;Atherosclerosis

廣西科學研究與技術(shù)開發(fā)計劃項目(桂科能1598025-29)；廣西醫(yī)療衛(wèi)生適宜技術(shù)研究與開發(fā)課題(S201316-03)

541001廣西桂林市，桂林醫(yī)學院附屬醫(yī)院特需病區(qū)(胡迪聃，徐彤彤，王文艷)；臺州市中心醫(yī)院檢驗科(顧婉紅)

徐彤彤，541001廣西桂林市，桂林醫(yī)學院附屬醫(yī)院特需病區(qū)；E-mail：xutongtongguilin@163.com

R 544.1

A

10.3969/j.issn.1007-9572.2016.22.013

2016-04-08；

2016-06-16)