馬度芳(綜述),李 曉(審校)
(1.山東中醫(yī)藥大學(xué)第一臨床學(xué)院,濟(jì)南 250011; 2.山東中醫(yī)藥大學(xué)附屬醫(yī)院心內(nèi)科,濟(jì)南 250011)
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神經(jīng)營(yíng)養(yǎng)因子在糖尿病心臟神經(jīng)病變中的研究概述
馬度芳1△(綜述),李曉2※(審校)
(1.山東中醫(yī)藥大學(xué)第一臨床學(xué)院,濟(jì)南 250011; 2.山東中醫(yī)藥大學(xué)附屬醫(yī)院心內(nèi)科,濟(jì)南 250011)
摘要:心臟自主神經(jīng)病變是糖尿病的嚴(yán)重并發(fā)癥之一,神經(jīng)營(yíng)養(yǎng)因子,如神經(jīng)生長(zhǎng)因子(NGF)、生長(zhǎng)相關(guān)蛋白43(GAP-43)和睫狀神經(jīng)營(yíng)養(yǎng)因子(CNTF)等異常表達(dá)可造成心臟支配神經(jīng)的營(yíng)養(yǎng)和功能障礙,也是糖尿病心臟神經(jīng)病變的病理機(jī)制之一。NGF或CNTF的表達(dá)異常可造成交感神經(jīng)、迷走神經(jīng)和感覺(jué)神經(jīng)對(duì)心臟的支配功能異常,并與糖尿病時(shí)心臟自主神經(jīng)重構(gòu)有關(guān)。而GAP-43表達(dá)增加表明心臟神經(jīng)損傷后出現(xiàn)再生。研究糖尿病時(shí)神經(jīng)營(yíng)養(yǎng)因子的變化趨勢(shì),并對(duì)其進(jìn)行有效干預(yù)可以防治糖尿病心臟神經(jīng)病變,為開(kāi)發(fā)治療糖尿病心臟神經(jīng)病變的藥物或技術(shù)提供新的線索和依據(jù)。
關(guān)鍵詞:糖尿?。恍呐K自主神經(jīng)病變;神經(jīng)營(yíng)養(yǎng)因子;神經(jīng)生長(zhǎng)因子;生長(zhǎng)相關(guān)蛋白43;睫狀神經(jīng)營(yíng)養(yǎng)因子
糖尿病神經(jīng)病變?cè)谔悄虿』颊咧械陌l(fā)病率為60%~70%,主要表現(xiàn)為遠(yuǎn)端對(duì)稱性感覺(jué)神經(jīng)病和自主神經(jīng)病變[1-2]。神經(jīng)營(yíng)養(yǎng)因子是一種對(duì)中樞和周圍神經(jīng)系統(tǒng)有營(yíng)養(yǎng)作用的小分子多肽或蛋白質(zhì),在出生前,神經(jīng)營(yíng)養(yǎng)因子的作用是維持神經(jīng)系統(tǒng)的正常發(fā)育和神經(jīng)元的存活,并可誘導(dǎo)神經(jīng)突起的生長(zhǎng)方向,在成熟個(gè)體,神經(jīng)營(yíng)養(yǎng)因子對(duì)神經(jīng)系統(tǒng)的可塑性、結(jié)構(gòu)的完整和功能的維持具有重要調(diào)節(jié)作用[3]。神經(jīng)營(yíng)養(yǎng)因子的水平和活性改變是糖尿病神經(jīng)病變的原因之一[4],因此對(duì)某些神經(jīng)營(yíng)養(yǎng)因子進(jìn)行有利干預(yù)可以減緩糖尿病自主神經(jīng)病變的進(jìn)展?,F(xiàn)就糖尿病動(dòng)物模型和糖尿病患者體內(nèi)的幾種神經(jīng)營(yíng)養(yǎng)因子變化進(jìn)行闡述。
1神經(jīng)生長(zhǎng)因子
神經(jīng)生長(zhǎng)因子(never growth factor,NGF)產(chǎn)生于神經(jīng)所支配的器官中,逆向轉(zhuǎn)運(yùn)到神經(jīng)元中發(fā)揮作用。NGF在心臟中表達(dá)水平與交感神經(jīng)支配密度相關(guān),NGF水平降低可使交感神經(jīng)元數(shù)量減少,而NGF過(guò)度表達(dá)也會(huì)導(dǎo)致交感神經(jīng)高支配[5]。Hellweg和Hartung[6]在鏈脲佐菌素(streptozotocin,STZ)糖尿病大鼠的心臟中發(fā)現(xiàn),于成模第6周時(shí)心房中NGF上升至最大值,為對(duì)照組的(145.4±13.0)%,之后持續(xù)下降。在心室中,NGF水平于成模第3周上升至最大值,為對(duì)照組的(185.6±26.0)%,而第12周時(shí)顯著下降,在第6個(gè)月時(shí)心室中的NGF降至對(duì)照組的(50.9±7.0)%。同樣,Meloni等[7]也發(fā)現(xiàn)STZ 1型糖尿病小鼠在第12周時(shí)左心室中NGF信使RNA表達(dá)較對(duì)照組明顯降低。因此,可推斷NGF在STZ大鼠心臟中呈現(xiàn)先升后降的變化趨勢(shì)。
Schmid等[8]利用11C標(biāo)記間羥基麻黃素來(lái)標(biāo)記STZ大鼠心臟交感神經(jīng)異構(gòu)情況,并與局部心臟中的NGF水平變化對(duì)照發(fā)現(xiàn),在成模6個(gè)月后,STZ大鼠左心室近端心肌11C間羥基麻黃素滯留較對(duì)照組降低9%,遠(yuǎn)端降低33%。STZ大鼠左心室近端心肌NGF水平與對(duì)照組相比降低52%,而遠(yuǎn)端降低82%。在第9個(gè)月時(shí),STZ大鼠近端與遠(yuǎn)端心肌11C 間羥基麻黃素滯留均降低42%,且近端與遠(yuǎn)端心肌的NGF水平也降低相同程度,表明左心室交感神經(jīng)分布由近及遠(yuǎn)的減少可能與心肌中的NGF水平階梯式降低相關(guān),因此NGF的水平及分布改變會(huì)增加心臟中交感神經(jīng)支配的異質(zhì)性。近來(lái),人們利用轉(zhuǎn)基因技術(shù)阻止NGF降低,如Ieda等[9]用STZ分別誘導(dǎo)野生型小鼠和NGF轉(zhuǎn)基因小鼠后發(fā)現(xiàn),野生型小鼠第8周時(shí)心臟中降鈣素基因相關(guān)肽(一種感覺(jué)神經(jīng)的標(biāo)志物)免疫組織化學(xué)陽(yáng)性反應(yīng)無(wú)變化,而在第16周時(shí)下降至53%,相應(yīng)地,NGF信使RNA在第8周時(shí)無(wú)變化而在第16周時(shí)下降至57%,表明NGF表達(dá)降低與糖尿病導(dǎo)致的心臟痛覺(jué)感覺(jué)神經(jīng)支配下降有關(guān)。而這種變化在心臟能充分表達(dá)NGF的轉(zhuǎn)基因小鼠中可以改善,并且在心肌缺血時(shí)心臟傳入神經(jīng)的電生理活動(dòng)表明NGF轉(zhuǎn)基因小鼠心臟中感覺(jué)神經(jīng)支配功能修復(fù)。
除對(duì)神經(jīng)的保護(hù)作用外,NGF還可通過(guò)自分泌或旁分泌機(jī)制作用于心血管內(nèi)皮細(xì)胞,維持內(nèi)皮細(xì)胞的存活及其正常功能[10]。Meloni等[7]證明,接受NGF轉(zhuǎn)基因治療的小鼠心肌中微血管病變程度和心肌間質(zhì)纖維化程度明顯低于未治療的小鼠,NGF轉(zhuǎn)基因治療的STZ小鼠未出現(xiàn)糖尿病心肌病。由此可見(jiàn),心臟中NGF水平降低與糖尿病心臟自主神經(jīng)病變及糖尿病心肌病有密切關(guān)系,阻止心肌中NGF降低可為臨床治療與糖尿病相關(guān)的心臟疾病提供線索。
2生長(zhǎng)相關(guān)蛋白
生長(zhǎng)相關(guān)蛋白43(growth association protein 43,GAP-43)是一種在神經(jīng)發(fā)育和再生過(guò)程中與軸突生長(zhǎng)有關(guān)的膜結(jié)合磷酸化蛋白,它參與神經(jīng)軸突的生長(zhǎng)和突觸的形成,并與神經(jīng)元細(xì)胞膜構(gòu)架有關(guān)。對(duì)家兔心肌梗死后梗死周邊的交感神經(jīng)密度和GAP-43表達(dá)程度進(jìn)行研究,發(fā)現(xiàn)梗死3 d后交感神經(jīng)支配密度下降,而GAP-43表達(dá)顯著增加,在7 d后梗死周邊的交感神經(jīng)密度和GAP-43均增加,且兩者呈現(xiàn)顯著相關(guān)性,表明GAP-43可作為神經(jīng)損傷和修復(fù)的標(biāo)志物參與交感神經(jīng)重構(gòu)[11]。
Vo和Tomlinson[12]研究發(fā)現(xiàn),在STZ大鼠右心房中GAP-43蛋白水平比正常大鼠高,而且一直持續(xù)6周多。相反,Wang等[13]利用免疫組織化學(xué)法發(fā)現(xiàn),STZ大鼠心臟中GAP-43較正常減少。造成這種相反結(jié)果的原因可能與研究方法不同有關(guān)。GAP-43為交感神經(jīng)芽生的標(biāo)志物,糖尿病時(shí)心臟中GAP-43過(guò)度表達(dá)標(biāo)志著神經(jīng)損傷后出現(xiàn)重構(gòu)現(xiàn)象。
3睫狀神經(jīng)營(yíng)養(yǎng)因子
睫狀神經(jīng)營(yíng)養(yǎng)因子(ciliary neurotrophic factor,CNTF)最初是從雞胚眼的提取物中分離出來(lái)的蛋白質(zhì),具有營(yíng)養(yǎng)神經(jīng)、抗神經(jīng)病變、促進(jìn)神經(jīng)存活和調(diào)節(jié)能量代謝等功能[14]。研究發(fā)現(xiàn),在雞胚發(fā)育的第11~13日為副交感神經(jīng)支配雞胚心房,CNTF及其受體在發(fā)育的雞胚心臟中表達(dá)較高,雞胚第13日時(shí)心房中的CNTF受體信使RNA為第6日時(shí)的4倍,此時(shí)心房中的CNTF是心室的2.5倍,與心房中副交感神經(jīng)支配占優(yōu)勢(shì)相應(yīng)。而且,用CNTF培養(yǎng)的心房肌細(xì)胞中的膽堿能受體比未用CNTF的增加2倍,因此CNTF與迷走神經(jīng)的發(fā)育和再生有關(guān)[15]。CNTF對(duì)受損的迷走神經(jīng)有修復(fù)作用,因此可為進(jìn)一步研究CNTF與糖尿病心臟迷走神經(jīng)病變的關(guān)系奠定基礎(chǔ)。
除迷走神經(jīng)外,CNTF還可促進(jìn)軀體運(yùn)動(dòng)神經(jīng)和感覺(jué)神經(jīng)的軸突再生,Saleh等[16]發(fā)現(xiàn)給予CNTF可提高STZ大鼠受損坐骨神經(jīng)的傳導(dǎo)能力,加速受損感覺(jué)神經(jīng)再生。CNTF可預(yù)防糖尿病大鼠的痛溫覺(jué)減退[17]。另外,在視神經(jīng)損傷的糖尿病大鼠,CNTF可減緩視網(wǎng)膜神經(jīng)節(jié)死亡[18]??梢?jiàn),CNTF對(duì)于糖尿病引起的外周神經(jīng)病變有潛在治療作用。
目前認(rèn)為,CNTF除對(duì)神經(jīng)的保護(hù)作用外,還可在體內(nèi)發(fā)揮其他抗糖尿病的作用[19]。研究顯示,CNTF可減輕細(xì)胞因子誘導(dǎo)的胰島細(xì)胞凋亡,增加存活的胰島β細(xì)胞數(shù)量,同時(shí)可降低胰島素的清除率[20]。最近的研究顯示,CNTF可用于治療肥胖,一方面通過(guò)調(diào)節(jié)下丘腦抑制對(duì)食物的攝取[21],另一方面可通過(guò)促進(jìn)線粒體合成,提高脂肪組織的氧化能力來(lái)減少脂肪的堆積[22]。另外,CNTF具有與瘦素相似的作用,但無(wú)“瘦素抵抗”,它可以增加高脂飼養(yǎng)小鼠的胰島素敏感性[23]。由此推測(cè),CNTF對(duì)于防治糖尿病及其引發(fā)的神經(jīng)病變具有重要作用,它對(duì)糖尿病時(shí)心臟迷走神經(jīng)損傷是否有治療價(jià)值有待于進(jìn)一步研究。
4神經(jīng)營(yíng)養(yǎng)因子在糖尿病患者中的相關(guān)研究
研究糖尿病患者體內(nèi)神經(jīng)營(yíng)養(yǎng)因子變化可為治療糖尿病神經(jīng)病變提供線索。Kim等[24]研究發(fā)現(xiàn),伴周圍神經(jīng)病變的糖尿病患者血漿中的NGF比無(wú)神經(jīng)病變的糖尿病患者高,而在有周圍神經(jīng)病變的患者,血漿NGF水平與神經(jīng)病變程度呈負(fù)相關(guān),認(rèn)為血漿中的NGF升高不是糖尿病周圍神經(jīng)病變的促使因素,而是病變的結(jié)果??梢?jiàn),伴隨糖尿病神經(jīng)病的發(fā)展,NGF在血漿中的水平是變化的,但目前的研究未能闡述NGF變化的原因,且NGF準(zhǔn)確的變化趨勢(shì)也需更多的證據(jù)加以確定。
Bursova等[25]研究了2型糖尿病患者皮膚神經(jīng)纖維中的GAP-43表達(dá),認(rèn)為GAP-43減少可作為2型糖尿病患者早期神經(jīng)損傷后再生的標(biāo)志物,GAP-43在皮膚神經(jīng)結(jié)構(gòu)中表達(dá)減少可作為2型糖尿病神經(jīng)病變進(jìn)展到表皮下神經(jīng)結(jié)構(gòu)受損的標(biāo)志。關(guān)于CNTF,美國(guó)Kegenerou和Synergen公司最早開(kāi)展CNTF藥物研究,且已證明該藥物在促進(jìn)運(yùn)動(dòng)神經(jīng)元發(fā)育并防止受損運(yùn)動(dòng)神經(jīng)元退變方面具有獨(dú)特的作用[23],因此CNTF有望成為治療糖尿病神經(jīng)病變的新型藥物。
5結(jié)語(yǔ)
神經(jīng)營(yíng)養(yǎng)因子NGF和CNTF的異常表達(dá)和分布是糖尿病心臟神經(jīng)病變的病理機(jī)制之一,而GAP-43過(guò)度表達(dá)標(biāo)志著心臟自主神經(jīng)損傷后出現(xiàn)重構(gòu)現(xiàn)象。因此,干預(yù)神經(jīng)營(yíng)養(yǎng)因子的水平和分布可為治療糖尿病心臟神經(jīng)病變提供新的思路,而研究糖尿病心臟自主神經(jīng)病變時(shí)相關(guān)神經(jīng)營(yíng)養(yǎng)因子的變化為開(kāi)發(fā)治療糖尿病心臟自主神經(jīng)病變的藥物或技術(shù)提供新的線索。
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Research on Changes of Neurotrophic Factors in Process of Diabetic Cardiac Autonomic Neuropathy
MADu-fang1,LIXiao2(1.TheFirstClinicalCollege,ShandongUniversityofTraditionalChineseMedicine,Jinan250011,China; 2.DepartmentofCardiology,AffiliatedHospitalofShandongUniversityofTraditionalChineseMedicine,Jinan250011,China)
Abstract:The expression of neurotrophic factors such as nerve growth factor(NGF),growth association protein 43(GAP-43)and ciliary neurotrohic factor(CNTF)is abnormal in the process of diabetic neuropathy,which is one of the most important pathological basis of diabetic cardiac neuropathy.Abnormal NGF or CNTF expression is related to the dysfunction of cardiac sympathetic,parasympathetic and sensory nerves,and also participates in the cardiac autonomic nerve remodeling.The elevated expression of GAP-43 is a marker of nerve sprouting.Therefore,it is essential to study the variation trend of neurotrophic factors and regulate the abnormal change in the process of prevention and treatment of cardiac neuropathy,which may also provide new clue and reference for the development of medication or technology to treat diabetic cardiac neuropathy.
Key words:Diabetes; Cardiac autonomic neuropathy; Neurotrophic factors; Nerve growth factor; Growth association protein 43; Ciliary neurotrohic factor
基金項(xiàng)目:國(guó)家自然科學(xué)基金(81072962)
doi:10.3969/j.issn.1006-2084.2015.03.001
中圖分類號(hào):R11
文獻(xiàn)標(biāo)識(shí)碼:A
文章編號(hào):1006-2084(2015)03-0385-03