張炙萍 綜述,王 蓉,盛樹(shù)力 審校

噻唑烷二酮類(thiazolidinediones,TZDs)藥物包括羅格列酮(rosiglitazone,RSG)、比格列酮(pioglitazone,PIO)、曲格列酮(troglitazone,T RO),T RO上市后因?yàn)閲?yán)重的肝臟毒性已退出市場(chǎng)。它們屬于胰島素增敏劑,通過(guò)增加脂肪、骨骼肌、肝臟組織的胰島素敏感性降低胰島素抵抗,改善2型糖尿病患者的血糖和血脂異常[1～3]。其抗糖尿病作用是通過(guò)結(jié)合并激活過(guò)氧化物酶體增殖激活受體γ(peroxisome proliferator-activated receptor-γ,PPAR-γ)介導(dǎo)的,PPAR-γ屬于核受體超家族的轉(zhuǎn)錄因子,主要在脂肪組織表達(dá)[4],在其他組織也觀察到低水平PPAR-γ受體mRNA的存在[5]。研究發(fā)現(xiàn),此類藥物對(duì)心血管系統(tǒng)也有改善作用,可改善心肌代謝,預(yù)防心肌肥大,改善心肌缺血/再灌注損傷。本文從以上三個(gè)方面闡述TZDs類的心肌保護(hù)作用,并探討可能的機(jī)制。

1 TZDs類可改善心肌代謝

健康個(gè)體的心肌在空腹時(shí)以游離脂肪酸(free fatty acid,FFAs)作為主要能源,飽食狀態(tài)下以葡萄糖為主要能源[6];在糖尿病和胰島素抵抗?fàn)顟B(tài)下,心肌消耗過(guò)量的FFAs而降低了葡萄糖和乳酸的代謝[7～9]。FFAs氧化增加導(dǎo)致甘油三酯及FFAs氧化中間產(chǎn)物ceramides生成增加[9～11],這些產(chǎn)物對(duì)心肌不利,增加活性氧(reactive oxygen species,ROS)的生成,上調(diào)誘導(dǎo)型一氧化氮合酶(inducible nitric oxide synthase,iNOS)活性和凋亡增強(qiáng)。

為了增加心肌葡萄糖的攝取,必須增強(qiáng)葡萄糖的跨膜轉(zhuǎn)運(yùn),因?yàn)榇谁h(huán)節(jié)為葡萄糖利用的限速步驟。而葡萄糖轉(zhuǎn)運(yùn)能力與葡萄糖轉(zhuǎn)運(yùn)子(glucose transporter,GluT)尤其是GluT4的蛋白含量相關(guān)。最初發(fā)現(xiàn),TZDs類可以影響葡萄糖轉(zhuǎn)運(yùn)子在脂肪和骨骼肌的表達(dá)和功能[12,13]。而它們對(duì)心肌也有類似的作用,例如Sidell等[14]研究發(fā)現(xiàn),Zucker肥胖大鼠心肌GluT4蛋白表達(dá)下降,胰島素刺激的心肌葡萄糖攝取受損,RSG治療使GluT4增加,心肌葡萄糖攝取恢復(fù)正常。在體外,用T RO與大鼠心肌細(xì)胞共培養(yǎng)20 h,可使GluT4蛋白表達(dá)增加[15];RSG干預(yù)也可使鏈尿佐菌素(streptozotocin)誘導(dǎo)的2型糖尿病大鼠心肌GluT4表達(dá)增加[16]。臨床研究發(fā)現(xiàn),RSG治療可以改善2型糖尿病合并冠心病患者的胰島素敏感性和心肌缺血區(qū)和非缺血區(qū)的葡萄糖攝取[17]。

以上結(jié)果說(shuō)明,TZDs可通過(guò)改善心肌葡萄糖代謝,易化葡萄糖的貯備及利用。而此種保護(hù)作用的具體機(jī)制并不清楚,可能與血漿FFAs活性受到抑制有關(guān)。在胰島素抵抗?fàn)顟B(tài)下,高濃度的FFAs激活蛋白激酶C的活性,后者可抑制PI3K通路,從而造成GluT4轉(zhuǎn)位的下降[18,19]。TZDs治療可降低血漿FFAs水平,改善骨骼肌的胰島素敏感性,其對(duì)心肌可能也有類似作用。

2 TZDs類可預(yù)防心肌肥大

臨床研究發(fā)現(xiàn),心肌肥大不但是心衰前心肌的一種代償狀態(tài),更是很多疾病如心肌缺血、心律不齊和猝死的獨(dú)立危險(xiǎn)因素。因此,控制心肌肥大的進(jìn)展尤為重要。研究發(fā)現(xiàn),TZDs作用于培養(yǎng)的心肌細(xì)胞可抑制血管緊張素Ⅱ(angiotensinⅡ)誘導(dǎo)的α-肌動(dòng)蛋白(α-actin)和心鈉肽(atrial natriuretic peptide)基因表達(dá)上調(diào)及細(xì)胞表面積增加[20];Ye等[21]研究發(fā)現(xiàn),PIO可減少肥大心肌細(xì)胞的表面積,抑制3H-亮氨酸進(jìn)入細(xì)胞,使細(xì)胞內(nèi)蛋白合成速率下降,上調(diào)PPAR-γmRNA的表達(dá),使炎性因子白細(xì)胞介素(IL)-1β和IL-6 mRNA表達(dá)減少。

以上結(jié)果說(shuō)明,PPAR-γ通路參與了心肌肥大的抑制,可能與PPAR-γ的激活及隨后的抗炎效應(yīng)相關(guān)。一系列的轉(zhuǎn)錄因子也參與了此過(guò)程,如激活蛋白-1(activator protein-1,AP-1)、信號(hào)轉(zhuǎn)導(dǎo)及轉(zhuǎn)錄活化因子(signal transducers and activators of transcription,STAT s)等。AP-1可激活很多基因,如心肌肥大特征性基因心鈉肽和內(nèi)皮素-1(endothelin-1,ET-1),后者在體外可誘導(dǎo)心肌肥大[22,23]。STATs在細(xì)胞因子信號(hào)通路中發(fā)揮重要作用[24],有報(bào)道STAT3在心肌細(xì)胞中激活并通過(guò)一種信號(hào)轉(zhuǎn)導(dǎo)蛋白gp130介導(dǎo)了心肌肥大[25]。而PPAR-γ激動(dòng)劑可通過(guò)干擾AP-1、STAT信號(hào)通路下調(diào)單核細(xì)胞的炎癥反應(yīng)[26],通過(guò)抑制AP-1信號(hào)通路抑制人類血管內(nèi)皮細(xì)胞ET-1的產(chǎn)生[27]。因此TZDs可能通過(guò)抑制多種轉(zhuǎn)錄因子如AP-1、STAT3活性抑制心肌肥大的進(jìn)展。

3 TZDs類可改善心肌缺血/再灌注損傷

心肌缺血/再灌注損傷是指在短時(shí)間心肌血供中斷,一定時(shí)間內(nèi)恢復(fù)血供,原缺血心肌發(fā)生較血供恢復(fù)前更嚴(yán)重的損傷[28]。隨著心臟移植、體外循環(huán)、冠脈搭橋以及血管造影介入治療的發(fā)展,為了防治心肌缺血/再灌注損傷,學(xué)者們進(jìn)行了多方面的研究,尤以預(yù)處理為熱點(diǎn),預(yù)處理包括缺血預(yù)處理和藥物預(yù)處理,由于缺血預(yù)處理本身也是一種損傷性因素,因此應(yīng)用藥物預(yù)處理防治缺血/再灌注損傷具有更好的發(fā)展前景。

Yue等[29]研究發(fā)現(xiàn),在缺血前給予Zucker肥胖大鼠口服RSG,不但降低血糖、甘油三酯及FFAs的水平,還能增加心肌葡萄糖的氧化;RSG治療使大鼠心肌細(xì)胞凋亡的數(shù)量及心肌梗死面積減少58%和46%,心肌收縮功能障礙改善。以上作用可能(1)與TZDs的胰島素增敏作用相關(guān)。因?yàn)镽SG治療使心肌蛋白激酶AKT磷酸化及AKT激酶的活性增強(qiáng),用wortmannin(PI3K抑制劑)阻斷治療組大鼠的胰島素-AKT信號(hào)通路,導(dǎo)致RSG的心肌保護(hù)作用降低。(2)與血管緊張素(angiotensin,AT)受體有關(guān)。研究發(fā)現(xiàn)與正常對(duì)照組相比,RSG治療組大鼠心肌AT1受體表達(dá)減少,而AT2受體表達(dá)顯著升高,并且伴隨著p42/44 MAPK的抑制[30]。以前的研究顯示AT1受體在缺血/再灌注時(shí)過(guò)表達(dá)[31],而AT1受體拮抗劑對(duì)于缺血/再灌注心肌具有保護(hù)作用[32],此種作用部分是通過(guò)上調(diào)AT2受體的表達(dá)實(shí)現(xiàn)的[33],AT2受體又可以激活蛋白酪氨酸激酶,使p42/44 MAPK的蘇氨酸和酪氨酸殘基去磷酸化[34]。p42/44 MAPK活性的抑制可能拮抗缺血/再灌注過(guò)程中血管緊張素及AT1受體激活的心肌損傷作用。RSG介導(dǎo)的AT2受體上調(diào)及AT1受體下調(diào)的機(jī)制不清,可能與降低缺血/再灌注過(guò)程中自由基的生成相關(guān)。(3)可能與一氧化氮(nitric oxide,NO)有關(guān)。Gonon等[35]研究發(fā)現(xiàn),與野生型小鼠心臟相比,RSG干預(yù)可增強(qiáng)左室功能的恢復(fù),增加缺血后冠狀動(dòng)脈的血流。RSG干預(yù)組內(nèi)皮一氧化氮合酶(endothelial nitric oxide synthase,eNOS)的表達(dá)量未受影響,但磷酸化-eNOS顯著增加,且使用 L-NNA(NOS的抑制劑)可顯著減弱RSG的心肌保護(hù)作用。eNOS在心血管系統(tǒng)中主要分布在內(nèi)皮細(xì)胞和心肌細(xì)胞中,其表達(dá)水平的高低影響著血管內(nèi)皮NO的產(chǎn)生,NO是一種內(nèi)皮源性的舒張因子,具有引起心臟血管平滑肌松弛的生理效應(yīng),導(dǎo)致供應(yīng)心肌的血管擴(kuò)張,增加心肌組織中的血液灌注量。Jones等[36]的研究顯示,eNOS轉(zhuǎn)基因大鼠缺血/再灌注損傷后心肌損傷的程度較非eNOS轉(zhuǎn)基因大鼠輕,由此推測(cè)eNOS對(duì)心肌缺血/再灌注損傷具有保護(hù)作用。(4)與抑制細(xì)胞凋亡及基質(zhì)金屬蛋白酶-2(matrix metalloproteinase-2,MMP-2)的表達(dá)相關(guān)。研究發(fā)現(xiàn),心肌缺血/再灌注過(guò)程中有不同程度的細(xì)胞凋亡現(xiàn)象,MMP-2因可分解細(xì)胞基底膜和細(xì)胞外基質(zhì)的骨架成分,主要在癌癥轉(zhuǎn)移過(guò)程中發(fā)揮重要作用。Cao等[37]采用原位末端標(biāo)記和瓊脂糖凝膠電泳證實(shí),缺血再灌注大鼠的心肌有典型的凋亡形態(tài)學(xué)改變和DNA梯狀電泳變,即再灌注損傷可導(dǎo)致心肌細(xì)胞凋亡。PIO治療組大鼠心肌細(xì)胞凋亡顯著減少,Bcl-2表達(dá)增加,Bax和Caspase-3表達(dá)減少,除此之外,PIO以劑量依賴方式增加PPAR-γmRNA和蛋白表達(dá),減少M(fèi)MP-2的表達(dá)。

另外,在TZDs的注冊(cè)臨床試驗(yàn)和臨床應(yīng)用中,人們觀察到接受TZDs與其他降糖藥物聯(lián)合治療的糖尿病患者中,踝部水腫和充血性心衰的發(fā)生率增加[38],可能與TZDs的血管舒張和水鈉潴留作用有關(guān)。由此臨床醫(yī)生對(duì)TZDs使用的心臟安全性提出質(zhì)疑。然而心衰的原因主要是TZDs引起的水鈉潴留所致的血容量增加,而不是 TZDs對(duì)心肌的毒性作用。臨床試驗(yàn)的數(shù)據(jù)顯示,使用TZDs的糖尿病患者充血性心衰的發(fā)生率較低(＜1%),且往往發(fā)生在TZDs尤其是RSG與胰島素聯(lián)合使用的情況下,此人群由于病程長(zhǎng)、并發(fā)癥多,患者本身心血管事件的發(fā)生率比一般糖尿病人群高,況且目前的研究無(wú)法證明TZDs的使用與充血性心衰存在直接關(guān)系。而且,TZDs對(duì)心血管系統(tǒng)具有多種有益作用[39],包括降低血壓、糾正血脂異常、改善內(nèi)皮結(jié)構(gòu)和功能、對(duì)抗炎癥、減少氧化應(yīng)激等。如PIO可減少心血管事件的發(fā)生,雖然增加發(fā)生充血性心衰的危險(xiǎn)度,但不提高死亡率[40]。本室的研究也發(fā)現(xiàn)RSG可以改善 2型糖尿病大鼠心肌的胰島素信號(hào)轉(zhuǎn)導(dǎo)異常。

綜上所述,TZDs藥物在心肌肥大、心肌缺血/再灌注損傷、心肌代謝等方面在心血管系統(tǒng)發(fā)揮一定的作用。這些作用雖然在2型糖尿病患者身上未被完全證實(shí),但其對(duì)心肌的保護(hù)作用,無(wú)疑對(duì)于2型糖尿病合并冠心病或高血壓患者是有益的,可減少心血管并發(fā)癥的發(fā)生,提高生存率。相關(guān)的臨床研究正在進(jìn)行中,其結(jié)果將有助于我們更好地理解TZDs類藥物對(duì)心臟的更多作用。

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