辛伐他汀对精氨酸加压素诱导大鼠心脏成纤维细胞增殖的影响及与小窝蛋白-1关系的研究
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摘要
研究背景及目的高血压是心血管疾病发生重要的危险因素,而左室肥厚(LVH)是导致高血压患者心血管事件发生率显著增加独立的危险因素,也是心脏功能由代偿向失代偿转化重要的病理表现。因此,心脏重构的发病机制和防治研究已成为国内外热点研究课题。现已明确,神经体液因素的异常激活是心脏重构发生的重要机制。精氨酸加压素(AVP)是与心血管疾病相关的重要的神经体液因子。已有研究显示,AVP可诱导新生大鼠心脏成纤维细胞(CFs)增殖,但对其诱导CFs增殖的信号转导过程仍不十分清楚。他汀类药物是目前防治高脂血症等高血压发病危险因素的主要药物之一。大量研究表明,他汀还具有防治心肌纤维化等诸多非调脂作用。研究发现,他汀类药物可抑制心肌细胞肥大以及CFs增殖和胶原合成;在自发性高血压大鼠模型中也证实,辛伐他汀(Sim)可延缓心肌肥厚的发展。这些研究提示,他汀类药物可调控心脏重构过程,但其分子机制仍不十分清楚。晚近研究发现,小窝是细胞膜上的结构,它不仅具有储存和运输内源性胆固醇的作用,同时还是细胞信号分子富集和信号转导的枢纽,其主要的标志蛋白——小窝蛋白对许多关键信号分子的活性状态起直接的负性调控作用。目前,他汀类药物抑制心肌纤维化过程是否受到细胞膜上的小窝的影响,目前尚不明确。小窝蛋白在CFs增殖中的变化尚为未知数。本课题研究AVP诱导成年大鼠CFs增殖情况及细胞外信号调节激酶(erk1/2)信号通路信号转导特点;Sim干预后erk1/2通路转导变化及其与小窝蛋白-1(cav1)的关系,探讨Sim抑制CFs增殖的信号转导作用,胆固醇变化对细胞膜上cav1表达的影响、对Sim干预AVP诱导的CFs增殖的作用,旨在阐明高血压心脏重构的发病机制,为他汀类药物防治心脏重构的分子机制提供新认识,亦为高血压心脏重构的防治提供新思路和理论依据。
研究方法本研究以体外培养的成年Sprague-Dawley (SD)大鼠CFs增殖为实验模型,采用[3H]-脱氧胸腺嘧啶苷酸掺入、流式细胞技术、体外激酶测定、Western blot、RT-PCR等方法和技术,观察和研究一下几项:(1) AVP对CFs增殖的影响;(2) PKC和erk1/2信号途径在AVP诱导CFs增殖中的作用;(3) Sim对CFs增殖的影响;(4) Sim对CFs增殖中PKC和erk1/2信号转导的调控效应;(5) cav1在Sim干预AVP诱导的CFs增殖中的变化;(6)外源性胆固醇对Sim调控CFs增殖的影响及其与cav1的关系。
研究结果(1)给予10-9～10-6 mol/L的AVP作用大鼠CFs 24 h后,随着AVP浓度的升高,CFs内的[3H]-TdR掺入率呈增加趋势。其中10~(-7) mol/L和10-6 mol/L的AVP干预组[3H]-TdR掺入率较对照组(100.0±5.1)%分别增加(172.0±4.0)%和(258.0±19.1)%(P < 0.05)。(2) AVP的V1受体阻断剂d(CH2)5[Tyr2(Me), Arg8]-vasopressin与0.1μmol/L的AVP共同干预大鼠CFs后的[3H]-TdR掺入率相当于空白对照组(100.0±6.0)%的(103.7±10.5)%,与10~(-7) mol/L AVP单独干预组的(173.5±5.1)%相比,统计学差异显著(P < 0.05)。而V2受体阻断剂desglycinamide-[d(CH2)5,D-Ile2, Ile4, Arg8]-vasopressin对AVP干预下大鼠CFs [3H]-TdR掺入率为(165.7±9.6)%,无明显影响(P > 0.05)。(3) AVP可上调CFs内erk1/2活性,其活性在5 min后达峰值,随后逐渐下降,至2 h时逐渐趋近于基线水平。(4) PD98059预处理后[3H]-TdR掺入率为(116.0±3.2)%,可明显抑制0.1μmol/L的AVP对大鼠CFs内的诱导作用(P < 0.05)。(5) 30 nmol/L的佛波酯(PMA)或0.1μmol/L的AVP干预大鼠CFs 5 min可显著增强大鼠CFs内的erk1/2活性,大鼠CFs内的erk1/2活性分别相当于对照组的(5.1±0.6)倍和(4.8±0.2)倍(P < 0.05)。而在用2.5μmol/L的PMA孵育大鼠CFs 24 h耗竭PKC后,大鼠CFs内的erk1/2活性相当于对照组的(2.1±0.3)倍,可显著抑制AVP诱导的erk1/2激活(P < 0.05)。(6) PKC抑制剂-钙感光蛋白可显著抑制0.1μmol/L的AVP诱导的大鼠CFs内[~3H]-TdR掺入率,相当于对照组的(116.0±3.2)%(P < 0.05)。(7) AVP可上调CFs内PKC活性,其活性在5 min后达峰值,至30 min时降至基线水平。(8) Ca2+螯合剂BAPTA与0.1μmol/L的AVP共同干预大鼠CF,其[~3H]-TdR掺入率相当于对照组的(154.2±5.9)%,与0.1μmol/L的AVP单独干预组的(168.8±10.1)%相比,没有显著影响(P > 0.05)。(9) 0.1μmol/L的AVP作用大鼠CFs 24 h后,CFs内的p27kip1蛋白表达量相当于对照组的(21.7±1.6)%,而细胞周期蛋白D1、A、E表达量分别相当于对照组的(5.7±0.5)倍、(5.4±0.5)倍和(6.0±0.7)倍,与对照组相比,均有显著的差异(P < 0.05)。PD98059可显著抑制AVP对p27kip1、细胞周期蛋白D1、A、E的干预效应,CFs内的p27kip1蛋白表达量相当于对照组的(102.0±5.0)%,细胞周期蛋白D1、A、E表达量分别相当于对照组的(1.4±0.2)倍、(2.1±0.3)倍和(3.0±0.3)倍,与AVP组相比,均P < 0.05。(10) 0.1μmol/L的AVP干预24 h后,细胞周期由G0/G1期进入S期增加,同时伴有细胞增殖指数(PI)增大(P<0.05)。PD98059可显著抑制AVP干预下的S期细胞百分比和PI指数增加(P<0.05)。(11)在用10-8～10-5 mol/L的Sim预处理24 h后,再用0.1μmol/L的AVP干预24 h,CFs的[~3H]-TdR掺入率分别相当于对照组的(172.0±9.8)%、(151.3±7.7)%、(128.3±7.6)%和(121.7±11.5)%,其中10~(-7)～10-5 mol/L的Sim组较AVP单独作用组的(176.8±9.3)%显著降低(P<0.05)。(12) 10-8～10-5 mol/L的Sim与10~(-7) mol/L的AVP联合作用CFs 24 h,随着刺激浓度的升高,CFs的S期细胞百分率和PI呈递减趋势,其中10~(-7)mol/L、10-6mol/L Sim与AVP共同干预组显著低于AVP单独作用组(均P<0.05);10-8 mol/L Sim与AVP共同干预组PI指数显著低于AVP单独作用组(P<0.05)。(13) 10-8～10-5 mol/L的Sim预处理大鼠CFs 24 h后,再用AVP干预大鼠CFs 5 min,CFs的erk1/2活性分别相当于对照组的(2.5±0.2)倍、(1.9±0.1)倍、(1.5±0.1)倍和(1.3±0.1)倍,其中10~(-7)～10-5 mol/L的Sim与AVP共同干预组CFs显著低于AVP单独作用组(P<0.05)。(14)在10-8～10-5 mol/L的Sim预处理大鼠CFs 24 h后,再用AVP干预大鼠CFs 5 min,CFs的PKC活性分别相当于AVP单独作用组的(24.8±2.4)%、(21.5±2.6)%、(17.3±1.8)%和(15.0±1.3)%,其中10-6 mol/L和10-5 mol/L的Sim与AVP共同干预组显著低于AVP单独作用组(P<0.05)。(15) MVA预处理可逆转10-6 mol/L的Sim对10~(-7) mol/L的AVP诱导作用,使CFs的[~3H]-TdR掺入率增加,相当于对照组的(166.2±6.8)%,PKC活性、erk1/2活性增加(均P<0.05)。(16)焦磷酸牛龙牛儿基牛龙牛儿酯(GGPP)可逆转10-6 mol/L的Sim对10~(-7) mol/L的AVP诱导作用,使CFs的[~3H]-TdR掺入率增加,相当于空白对照组的(159.8±7.7)% (P < 0.05);erk1/2激活,相当于空白对照组的(5.2±0.4)倍,而焦磷酸法尼酯(FPP)对AVP诱导的[~3H]-TdR掺入率增加和erk1/2激活没有明显影响。(17) 10~(-7) mol/L的Sim可显著抑制10~(-7) mol/L AVP诱导的大鼠CFs内磷酸化肌球蛋白结合亚基(MBS-P)表达,相当于对照组的(1.9±0.1)倍(P<0.05)。(18)用10μmol/L的GGPP抑制剂GGTI或5μmol/L的ROK激酶特异性抑制剂Y27632预处理大鼠CFs 24 h后,继而加入10~(-7) mol/L的AVP干预5 min,大鼠CFs内erk1/2活性分别相当于AVP单独作用组的(41±4)%和(25±3)%,均较AVP单独作用组显著降低(P<0.05)。(19) cav1反义寡核苷酸可使大鼠CFs的[~3H]-TdR掺入率增加,相当于空白对照组的(172.0±4.2)%;erk1/2活性增加,相当于空白对照组的(2.3±0.3)倍;细胞周期蛋白D1、A、E的表达量增加,分别相当于空白对照组的(9.3±0.2)倍、(7.6±0.4)倍和(9.1±0.4)倍,p27kip1的表达量下降,相当于空白对照组的(16.8±2.3)%(均P < 0.05)。(20) 10-9～10-6 mol/L的AVP干预CFs 24 h后,cav1蛋白表达量分别相当于AVP单独作用组的(86.7±4.6)%、(79.0±8.6)%、(59.7±3.7)%和(46.0±3.1)%。其中10~(-7) mol/L和10-6 mol/L的AVP干预组较对照组显著降低(P < 0.05)。(21)在用10~(-8)～10~(-5) mol/L的Sim与10~(-7) mol/L的AVP共同干预大鼠CFs 24 h后,cav1的表达量分别相当于AVP单独作用组的(88.7±2.7)%、(70.3±2.6)%、(60.7±2.2)%和(56.3±1.9)%。其中10~(-7)～10-5 mol/L的Sim与10~(-7) mol/L AVP共同作用组与AVP单独作用组相比较,均有显著差异(P < 0.05)。10~(-4) mol/L的MVA与10~(-7) mol/L的AVP共同干预组的cav1蛋白表达量较AVP单独作用组增加(P < 0.05)。(22) 10、20、30μg/ml胆固醇可使10-6mol/L的Sim与10~(-7)mol/L AVP联合作用组cav1蛋白表达量增加,相当于10~(-7) mol/L的AVP组的(108.3±4.3)%、(133.5±5.4)%和(146.0±5.8)%(P < 0.05)。(23)用10%的FBS加20μg/ml的胆固醇干预大鼠CFs 24 h后,大鼠CFs胞膜上cav1蛋白的表达量较单用FBS组无显著差异(P > 0.05)。而在用2%的MβCD预处理大鼠CFs 2 h以除去细胞膜上胆固醇,再加入2%的MβCD-胆固醇干预大鼠CFs 1 h后,CFs胞膜上cav1蛋白的表达量是单用MβCD预处理组的(2.7±0.2)倍,两组比较差异显著(P < 0.05)。(24)外源性胆固醇(10、20或30μg/ml胆固醇)干预大鼠CFs 1 h后,CFs内胆固醇含量分别为(18.4±1.2)μg胆固醇/mg蛋白、(22.0±1.1)μg胆固醇/mg蛋白和(26.4±1.3)μg胆固醇/mg蛋白,可增加2%的MβCD预处理以及10~(-7) mol/L的AVP与10-6 mol/L的Sim联合干预后大鼠CFs内的胆固醇含量,[~3H]-TdR掺入率降低,分别是未加胆固醇组的(74.0±4.8)%、(62.0±2.9)%和(35.8±4.3)%,而对10%的FBS干预后CFs内的胆固醇含量及[~3H]-TdR掺入率的增加影响较小。(25)在用10-6 mol/L的Sim预处理大鼠CFs 24 h的同时加用20μg/ml胆固醇,与AVP + Sim组的相比,可显著降低大鼠CFs内erk1/2活性,相当于对照组的(1.1±0.2)倍(P < 0.05)。
研究结论:(1) AVP可浓度依赖地促进成年SD大鼠CFs增殖。(2) AVP对成年SD大鼠CFs增殖地促进作用是由AVP的V1受体和PKC-erk1/2通路介导实现的。(3) AVP可通过erk1/2信号通路使p27Kip1表达减少、细胞周期蛋白D1、A和E的表达增加,细胞增殖指数增加,进而促进成年大鼠CFs增殖。(4) Sim可抑制AVP诱导的成年SD大鼠CFs增殖以及PKC-erk1/2通路的激活,这些效应可被MVA阻断。(5)外源性胆固醇可上调cav1蛋白表达,从而增强Sim对AVP诱导CFs增殖的抑制效应。
综上所述,该研究首次提出AVP可通过AVP的V1受体和PKC-erk1/2通路介导成年大鼠CFs增殖,该促增殖效应可被辛伐他汀所抑制。外源性胆固醇可上调cav1蛋白表达,从而增强Sim对AVP诱导CFs增殖的抑制效应。
Background and objective Hypertension is an important risk factor for the onset of cardiovascular diseases, whereas left ventricular hypertrophy (LVH) is an independent risk factor for the increased incidence of cardiovascular events and important pathological basis for the transition of cardiac function from a“compensated”state towards a“decompensated”one. Thus preventing and treating LVH has become one of the hot research issues in an international setting. It has now been established that the abnormal activation of neurohumoral factors is an important mechanism for the development of LVH. Arginine vasopressin (AVP) is a neurohumoral factor critically involved in cardiovascular disease. It has been shown that AVP can stimulate the proliferation of neonatal rat CFs, but it remains unclear how the signal transduction is achieved. 3-hydroxy- 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statins) is one of the major drug types that control the risk factors for hypertension, among which is hyperlipemia. However, a large pool of research has shown its other effects beyond cholesterol-lowing, including its role in the prevention of cardiac fibrosis. It was observed that statins could inhibit cardiomyocytes hypertrophy and cell proliferation and collagen synthesis of CFs and attenuate the LVH of spontaneously hypertensive rats (SHR). These observations indicate that statins can modulate the process of cardiac remodeling, but its mechanisms are less than well defined. caveolae are structures located in the cell membrane which harbor and transport endogenous cholesterol and serve as‘hinges’for the gathering and transduction of signaling molecules. Caveolin, the protein marker of caveolae, has direct negative modulatory effects on the activation of a variety of the key signaling molecules. It has been shown to inhibit the onset and development of cardiac fibrosis. However, it still remains unclear so far whether the inhibitory effect of statins on cardiac fibrosis is influenced by caveolae. No report has ever examined the changes of caveolin in the process of CFs proliferation. In the present study, we examined the potential proliferation-inducing effect of AVP on adult rat CFs and the involvement of erk1/2 and the changes in the activation of erk1/2 in the presence of Sim. The role of caveolin1 (cav1) is also investigated. In addition, we further explored the mechanisms for the inhibitory effect of Sim on CFs proliferation, the effects of the changes in the abundance of cholesterol in the cell membrane on the expression of cav1 and the modulation of AVP-induced CFs proliferation by Sim. Our objectives are to elucidate further the mechanisms of cardiac remodeling during hypertension and further the understanding of the molecular mechanisms for statins in the prevention and treatment of cardiac remodeling, and to provide new theoretical evidences and prevention and treatment approaches for LVH of hypertension.
Methods In this study, adult rat CFs isolated from Sprague-Dawley (SD) rats were cultured and used as experimental model. We employed [~3H]-thymidine incorporation, flow cytometry, in vitro kinase assay, Western blot analysis and RT-PCR in the present study to investigate: (1) Effect of AVP on CFs proliferation, (2) Role of PKC and erk1/2 pathway in the proliferatory effect of AVP on CFs proliferation, (3) Effect of Sim on CFs proliferation, (4) Modulatory effect of Sim on PKC and erk1/2 pathway during CFs proliferation, (5) Changes of cav1 in the modulation of AVP-induced CFs proliferation by Sim, (6) Effect of exogenous cholesterol on the modulation of Sim on CFs proliferation and its relationship with cav1 expression.
Results (1) Treating cells with 10-9 ~ 10-6 mol/L AVP increased [~3H]-thymidine incorporation in a concentration-dependent manner. 10~(-7) mol/L and 10-6 mol/L AVP increased [~3H]-thymidine incorporation by (72.0±4.0)% and(158.0±19.1)%, respectively(P < 0.05). (2) The effect of AVP on [~3H]-thymidine incorporation was abolished by incubating adult rat CFs with V1 receptor antagonist, d(CH2)5[Tyr2(Me), Arg8]-vasopressin, but not V2 receptor antagonist, desglycinamide-[d(CH2)5, D-Ile2, Ile4, Arg8]-vasopressin. (3) Erk1/2 activation could be induced by AVP (0.1μmol/L). The activation peaked at 5 min, with subsequent decline to near baseline level at 2 hour after the initiation of the stimulation. (4) PD98059 abolished the mitogenic effect of AVP(P < 0.05). (5) Phorbol 12-myristate 13-acetate (PMA, 30 nmol/L), as well as AVP for 5 min activated erk1/2 phosphorylation as measured by Western blots(P<0.05). Depleting PKC by chronic PMA incubation (2.5μmol/L, 24 h) abolished the stimulating effect of AVP on erk1/2 phosphorylation(P < 0.05). (6) Calphostin C, a PKC inhibitor, markedly reduced [~3H]-thymidine incorporation upon 0.1μmol/L AVP stimulation(P < 0.05). (7) PKC activation could readily be induced by AVP (0.1μM). The activation peaked at 5 min (approx. 3-fold induction, P<0.05) and subsequently declined to near baseline level at 30 min after the initiation of AVP stimulation. (8) Ca2+ chelating agent BAPTA had no significant effect on DNA synthesis stimulated by AVP (P>0.05). (9) The protein level of p27Kip1 was markedly attenuated upon AVP treatment to (21.7±1.6)% of control level, while expression of cyclins D1, A and E increased to (5.7±0.5)-fold,(5.4±0.5)-fold and (6.0±0.7)-fold of control(P < 0.05). Inhibiting erk1/2 activation by PD98059 (30μmol/L) abolished the effect of AVP on protein expression of p27Kip1 as well as cyclins D1, E and A. (10) 0.1μmol/L AVP induced cell cycle progression from G0/G1 into S phase, accompanied by increased proliferation index (PI) (P<0.05). The effects of AVP on G0/G1-S phase progression and PI were inhibited by PD98059. (11) When pretreating cells with simvastatin (10-8 ~ 10-5 mol/L) for 24 h before 10~(-7) mol/L AVP stimulation for another 24 h, [~3H]-thymidine incorporation in adult rat CFs were (172.0±9.8)%, (151.3±7.7)%, (128.3±7.6)%, and (121.7±11.5)%, respectively, of control, all being significantly lower (P<0.05) than AVP single-drug treated cells, except in the 10-8 mol/L simvastatin treated group. (12) When pretreating cells with simvastatin (10-8 ~ 10-5 mol/L) for 24 h before 10~(-7) mol/L AVP stimulation for another 24 h, cells in S stage and PI tended to decrease, with those of 10~(-7) mol/L and 10-6 mol/L Sim groups being significantly lower (both P<0.05) than AVP single-drug treated cells. And PI was significantly lower (P<0.05) in 10~(-7) ~ 10-5 mol/L Sim cells than in AVP single-drug treated cells. (13) When pretreating cells with simvastatin (10-8 ~ 10-5 mol/L) for 24 h before 10~(-7) mol/L AVP stimulation for 5 min, erk1/2 activation reached (2.5±0.2)-fold, (1.9±0.1)-fold, (1.5±0.1)-fold, and(1.3±0.1)-fold, respectively, over control level, being significantly lower (P<0.05) in 10~(-7) ~ 10-5 mol/L Sim cells than in AVP single-drug treated cells. (14) When pretreating cells with simvastatin (10-8 ~ 10-5 mol/L) for 24 h before 10~(-7) mol/L AVP stimulation for 5 min, PKC activation reached (24.8±2.4)%, (21.5±2.6)%, (17.3±1.8)% and(15.0±1.3)%, respectively, of control level, being significantly lower (P<0.05) in 10-6 mol/L and 10-5 mol/L Sim cells than in AVP single-drug treated cells. (15) MVA pretreatment reversed the inhibitory effect of 10-6mol/L simvastatin on 10~(-7)mol/L AVP induced increase in [~3H]-thymidine incorporation and PKC and erk1/2 activation. (16) Geranylgeranyl pyrophosphate (GGPP) reversed the inhibitory effect of 10-6mol/L simvastatin on 10~(-7)mol/L AVP induced increase in [~3H]-thymidine incorporation and erk1/2 activation, whereas farnesyl pyrophosphate (FPP) had no significant effect. (17) 10~(-7) mol/L simvastatin significantly inhibited 10~(-7) mol/L AVP-induced increase in MBS-P expression(P<0.05). (18) Pretreating cells with 10μmol/L GGTI or 5μmol/L Y27632 for 24 h before 10~(-7) mol/L AVP stimulation for 5 min significantly inhibited the AVP-induced erk1/2 activation (P<0.05). (19) Cav1 antisense oligonucleotides significantly increased [~3H]-thymidine incorporation, PKC and erk1/2 activation and the expression of cyclins D1, A and E in CFs, and decreased the expression of p27kip1 (all P < 0.05). (20) The cav1 expression in CFs were (86.7±4.6)%, (79.0±8.6)%, (59.7±3.7)% and (46.0±3.1)% of control when treating cells with 10-9 ~ 10-6 mol/L AVP, with the expression levels in 10~(-7) mol/L and 10-6 mol/L AVP groups being significantly lower than that of control (P < 0.05). (21) When pretreating cells with simvastatin (10-8 ~ 10-5 mol/L) for 24 h before 10~(-7) mol/L AVP stimulation for 24 h, cav1 expression were (88.7±2.7)%, (70.3±2.6)%,(60.7±2.2)% and (56.3±1.9)% of AVP single-drug treated cells, respectively, being significantly lower (P<0.05) in 10~(-7) ~ 10-5 mol/L Sim cells than in AVP single-drug treated cells. The addition of 10-4 mol/L MVA to 10~(-7) mol/L AVP significantly increased cav1 expression (P < 0.05). (22) 10μg/ml, 20μg/ml and 30μg/ml cholesterol significantly increased cav1 expression in cells treated with 10-6mol/L simvastatin and 10~(-7)mol/L AVP (all P < 0.05). (23) When cells were incubated with 10% FBS, the addition of 20μg/ml cholesterol showed no apparent effect on cav1 protein expression (P > 0.05). However, when cells were incubated with 2% Methyl-β-cyclodextrin (MβCD), a maneuver to deplete cells of cholesterol, the restoration of cholesterol by MβCD-cholesterol complex (containing 20μg/ml cholesterol) caused a (2.7±0.2)-fold increase from the cholesterol-depleted condition (P < 0.05). (24) Exogenous cholesterol increased the cholesterol content in cells treated with 2% MβCD and 10-7 mol/L AVP combined with 10-6 mol/L simvastatin. Exogenous cholesterol also inhibited the increase in [3H]-thymidine incorporation upon 2% MβCD treatment, whereas it had little effects on cellular cholesterol and the increase in [3H]-thymidine incorporation when cells were treated with 10% FBS. (25) Erk1/2 activation was significantly attenuated when 20μg/ml cholesterol was added simultaneously with 10-6 mol/L simvastatin to 10-7 mol/L AVP treated cells when compared with AVP and simvastatin treated cells (P < 0.05).
Conclusions (1) AVP acts as a growth-factor for adult rat CFs. (2) The mitogenic effect of AVP is mediated via type 1 receptor and PKC–erk1/2 pathway. (3) AVP modulates the expression of cell cycle regulatory proteins p27Kip1 and cyclins D1, A and E, which lie down-stream of erk1/2 activation, and induces cell cycle progression of adult rat CFs. (4) Simvastatin inhibits AVP induced CFs proliferation, PKC and erk1/2 pathway activation, an effect that can be reversed by MVA. (5) Cav1 restoration by cholesterol enhances the inhibitory effect of simvastatin on AVP-induced CFs proliferation.
In summary, AVP can stimulate the proliferation of adult rat CFs via type 1 receptor and PKC–erk1/2 pathway, an effect can be inhibited by simvasatin. The inhibitory effect of simvastatin on AVP-induced CFs proliferation can be enhanced by exogenous cholesterol via the induction of cav1 exression.
研究方法本研究以体外培养的成年Sprague-Dawley (SD)大鼠CFs增殖为实验模型,采用[3H]-脱氧胸腺嘧啶苷酸掺入、流式细胞技术、体外激酶测定、Western blot、RT-PCR等方法和技术,观察和研究一下几项:(1) AVP对CFs增殖的影响;(2) PKC和erk1/2信号途径在AVP诱导CFs增殖中的作用;(3) Sim对CFs增殖的影响;(4) Sim对CFs增殖中PKC和erk1/2信号转导的调控效应;(5) cav1在Sim干预AVP诱导的CFs增殖中的变化;(6)外源性胆固醇对Sim调控CFs增殖的影响及其与cav1的关系。
研究结果(1)给予10-9～10-6 mol/L的AVP作用大鼠CFs 24 h后,随着AVP浓度的升高,CFs内的[3H]-TdR掺入率呈增加趋势。其中10~(-7) mol/L和10-6 mol/L的AVP干预组[3H]-TdR掺入率较对照组(100.0±5.1)%分别增加(172.0±4.0)%和(258.0±19.1)%(P < 0.05)。(2) AVP的V1受体阻断剂d(CH2)5[Tyr2(Me), Arg8]-vasopressin与0.1μmol/L的AVP共同干预大鼠CFs后的[3H]-TdR掺入率相当于空白对照组(100.0±6.0)%的(103.7±10.5)%,与10~(-7) mol/L AVP单独干预组的(173.5±5.1)%相比,统计学差异显著(P < 0.05)。而V2受体阻断剂desglycinamide-[d(CH2)5,D-Ile2, Ile4, Arg8]-vasopressin对AVP干预下大鼠CFs [3H]-TdR掺入率为(165.7±9.6)%,无明显影响(P > 0.05)。(3) AVP可上调CFs内erk1/2活性,其活性在5 min后达峰值,随后逐渐下降,至2 h时逐渐趋近于基线水平。(4) PD98059预处理后[3H]-TdR掺入率为(116.0±3.2)%,可明显抑制0.1μmol/L的AVP对大鼠CFs内的诱导作用(P < 0.05)。(5) 30 nmol/L的佛波酯(PMA)或0.1μmol/L的AVP干预大鼠CFs 5 min可显著增强大鼠CFs内的erk1/2活性,大鼠CFs内的erk1/2活性分别相当于对照组的(5.1±0.6)倍和(4.8±0.2)倍(P < 0.05)。而在用2.5μmol/L的PMA孵育大鼠CFs 24 h耗竭PKC后,大鼠CFs内的erk1/2活性相当于对照组的(2.1±0.3)倍,可显著抑制AVP诱导的erk1/2激活(P < 0.05)。(6) PKC抑制剂-钙感光蛋白可显著抑制0.1μmol/L的AVP诱导的大鼠CFs内[~3H]-TdR掺入率,相当于对照组的(116.0±3.2)%(P < 0.05)。(7) AVP可上调CFs内PKC活性,其活性在5 min后达峰值,至30 min时降至基线水平。(8) Ca2+螯合剂BAPTA与0.1μmol/L的AVP共同干预大鼠CF,其[~3H]-TdR掺入率相当于对照组的(154.2±5.9)%,与0.1μmol/L的AVP单独干预组的(168.8±10.1)%相比,没有显著影响(P > 0.05)。(9) 0.1μmol/L的AVP作用大鼠CFs 24 h后,CFs内的p27kip1蛋白表达量相当于对照组的(21.7±1.6)%,而细胞周期蛋白D1、A、E表达量分别相当于对照组的(5.7±0.5)倍、(5.4±0.5)倍和(6.0±0.7)倍,与对照组相比,均有显著的差异(P < 0.05)。PD98059可显著抑制AVP对p27kip1、细胞周期蛋白D1、A、E的干预效应,CFs内的p27kip1蛋白表达量相当于对照组的(102.0±5.0)%,细胞周期蛋白D1、A、E表达量分别相当于对照组的(1.4±0.2)倍、(2.1±0.3)倍和(3.0±0.3)倍,与AVP组相比,均P < 0.05。(10) 0.1μmol/L的AVP干预24 h后,细胞周期由G0/G1期进入S期增加,同时伴有细胞增殖指数(PI)增大(P<0.05)。PD98059可显著抑制AVP干预下的S期细胞百分比和PI指数增加(P<0.05)。(11)在用10-8～10-5 mol/L的Sim预处理24 h后,再用0.1μmol/L的AVP干预24 h,CFs的[~3H]-TdR掺入率分别相当于对照组的(172.0±9.8)%、(151.3±7.7)%、(128.3±7.6)%和(121.7±11.5)%,其中10~(-7)～10-5 mol/L的Sim组较AVP单独作用组的(176.8±9.3)%显著降低(P<0.05)。(12) 10-8～10-5 mol/L的Sim与10~(-7) mol/L的AVP联合作用CFs 24 h,随着刺激浓度的升高,CFs的S期细胞百分率和PI呈递减趋势,其中10~(-7)mol/L、10-6mol/L Sim与AVP共同干预组显著低于AVP单独作用组(均P<0.05);10-8 mol/L Sim与AVP共同干预组PI指数显著低于AVP单独作用组(P<0.05)。(13) 10-8～10-5 mol/L的Sim预处理大鼠CFs 24 h后,再用AVP干预大鼠CFs 5 min,CFs的erk1/2活性分别相当于对照组的(2.5±0.2)倍、(1.9±0.1)倍、(1.5±0.1)倍和(1.3±0.1)倍,其中10~(-7)～10-5 mol/L的Sim与AVP共同干预组CFs显著低于AVP单独作用组(P<0.05)。(14)在10-8～10-5 mol/L的Sim预处理大鼠CFs 24 h后,再用AVP干预大鼠CFs 5 min,CFs的PKC活性分别相当于AVP单独作用组的(24.8±2.4)%、(21.5±2.6)%、(17.3±1.8)%和(15.0±1.3)%,其中10-6 mol/L和10-5 mol/L的Sim与AVP共同干预组显著低于AVP单独作用组(P<0.05)。(15) MVA预处理可逆转10-6 mol/L的Sim对10~(-7) mol/L的AVP诱导作用,使CFs的[~3H]-TdR掺入率增加,相当于对照组的(166.2±6.8)%,PKC活性、erk1/2活性增加(均P<0.05)。(16)焦磷酸牛龙牛儿基牛龙牛儿酯(GGPP)可逆转10-6 mol/L的Sim对10~(-7) mol/L的AVP诱导作用,使CFs的[~3H]-TdR掺入率增加,相当于空白对照组的(159.8±7.7)% (P < 0.05);erk1/2激活,相当于空白对照组的(5.2±0.4)倍,而焦磷酸法尼酯(FPP)对AVP诱导的[~3H]-TdR掺入率增加和erk1/2激活没有明显影响。(17) 10~(-7) mol/L的Sim可显著抑制10~(-7) mol/L AVP诱导的大鼠CFs内磷酸化肌球蛋白结合亚基(MBS-P)表达,相当于对照组的(1.9±0.1)倍(P<0.05)。(18)用10μmol/L的GGPP抑制剂GGTI或5μmol/L的ROK激酶特异性抑制剂Y27632预处理大鼠CFs 24 h后,继而加入10~(-7) mol/L的AVP干预5 min,大鼠CFs内erk1/2活性分别相当于AVP单独作用组的(41±4)%和(25±3)%,均较AVP单独作用组显著降低(P<0.05)。(19) cav1反义寡核苷酸可使大鼠CFs的[~3H]-TdR掺入率增加,相当于空白对照组的(172.0±4.2)%;erk1/2活性增加,相当于空白对照组的(2.3±0.3)倍;细胞周期蛋白D1、A、E的表达量增加,分别相当于空白对照组的(9.3±0.2)倍、(7.6±0.4)倍和(9.1±0.4)倍,p27kip1的表达量下降,相当于空白对照组的(16.8±2.3)%(均P < 0.05)。(20) 10-9～10-6 mol/L的AVP干预CFs 24 h后,cav1蛋白表达量分别相当于AVP单独作用组的(86.7±4.6)%、(79.0±8.6)%、(59.7±3.7)%和(46.0±3.1)%。其中10~(-7) mol/L和10-6 mol/L的AVP干预组较对照组显著降低(P < 0.05)。(21)在用10~(-8)～10~(-5) mol/L的Sim与10~(-7) mol/L的AVP共同干预大鼠CFs 24 h后,cav1的表达量分别相当于AVP单独作用组的(88.7±2.7)%、(70.3±2.6)%、(60.7±2.2)%和(56.3±1.9)%。其中10~(-7)～10-5 mol/L的Sim与10~(-7) mol/L AVP共同作用组与AVP单独作用组相比较,均有显著差异(P < 0.05)。10~(-4) mol/L的MVA与10~(-7) mol/L的AVP共同干预组的cav1蛋白表达量较AVP单独作用组增加(P < 0.05)。(22) 10、20、30μg/ml胆固醇可使10-6mol/L的Sim与10~(-7)mol/L AVP联合作用组cav1蛋白表达量增加,相当于10~(-7) mol/L的AVP组的(108.3±4.3)%、(133.5±5.4)%和(146.0±5.8)%(P < 0.05)。(23)用10%的FBS加20μg/ml的胆固醇干预大鼠CFs 24 h后,大鼠CFs胞膜上cav1蛋白的表达量较单用FBS组无显著差异(P > 0.05)。而在用2%的MβCD预处理大鼠CFs 2 h以除去细胞膜上胆固醇,再加入2%的MβCD-胆固醇干预大鼠CFs 1 h后,CFs胞膜上cav1蛋白的表达量是单用MβCD预处理组的(2.7±0.2)倍,两组比较差异显著(P < 0.05)。(24)外源性胆固醇(10、20或30μg/ml胆固醇)干预大鼠CFs 1 h后,CFs内胆固醇含量分别为(18.4±1.2)μg胆固醇/mg蛋白、(22.0±1.1)μg胆固醇/mg蛋白和(26.4±1.3)μg胆固醇/mg蛋白,可增加2%的MβCD预处理以及10~(-7) mol/L的AVP与10-6 mol/L的Sim联合干预后大鼠CFs内的胆固醇含量,[~3H]-TdR掺入率降低,分别是未加胆固醇组的(74.0±4.8)%、(62.0±2.9)%和(35.8±4.3)%,而对10%的FBS干预后CFs内的胆固醇含量及[~3H]-TdR掺入率的增加影响较小。(25)在用10-6 mol/L的Sim预处理大鼠CFs 24 h的同时加用20μg/ml胆固醇,与AVP + Sim组的相比,可显著降低大鼠CFs内erk1/2活性,相当于对照组的(1.1±0.2)倍(P < 0.05)。
研究结论:(1) AVP可浓度依赖地促进成年SD大鼠CFs增殖。(2) AVP对成年SD大鼠CFs增殖地促进作用是由AVP的V1受体和PKC-erk1/2通路介导实现的。(3) AVP可通过erk1/2信号通路使p27Kip1表达减少、细胞周期蛋白D1、A和E的表达增加,细胞增殖指数增加,进而促进成年大鼠CFs增殖。(4) Sim可抑制AVP诱导的成年SD大鼠CFs增殖以及PKC-erk1/2通路的激活,这些效应可被MVA阻断。(5)外源性胆固醇可上调cav1蛋白表达,从而增强Sim对AVP诱导CFs增殖的抑制效应。
综上所述,该研究首次提出AVP可通过AVP的V1受体和PKC-erk1/2通路介导成年大鼠CFs增殖,该促增殖效应可被辛伐他汀所抑制。外源性胆固醇可上调cav1蛋白表达,从而增强Sim对AVP诱导CFs增殖的抑制效应。
Background and objective Hypertension is an important risk factor for the onset of cardiovascular diseases, whereas left ventricular hypertrophy (LVH) is an independent risk factor for the increased incidence of cardiovascular events and important pathological basis for the transition of cardiac function from a“compensated”state towards a“decompensated”one. Thus preventing and treating LVH has become one of the hot research issues in an international setting. It has now been established that the abnormal activation of neurohumoral factors is an important mechanism for the development of LVH. Arginine vasopressin (AVP) is a neurohumoral factor critically involved in cardiovascular disease. It has been shown that AVP can stimulate the proliferation of neonatal rat CFs, but it remains unclear how the signal transduction is achieved. 3-hydroxy- 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statins) is one of the major drug types that control the risk factors for hypertension, among which is hyperlipemia. However, a large pool of research has shown its other effects beyond cholesterol-lowing, including its role in the prevention of cardiac fibrosis. It was observed that statins could inhibit cardiomyocytes hypertrophy and cell proliferation and collagen synthesis of CFs and attenuate the LVH of spontaneously hypertensive rats (SHR). These observations indicate that statins can modulate the process of cardiac remodeling, but its mechanisms are less than well defined. caveolae are structures located in the cell membrane which harbor and transport endogenous cholesterol and serve as‘hinges’for the gathering and transduction of signaling molecules. Caveolin, the protein marker of caveolae, has direct negative modulatory effects on the activation of a variety of the key signaling molecules. It has been shown to inhibit the onset and development of cardiac fibrosis. However, it still remains unclear so far whether the inhibitory effect of statins on cardiac fibrosis is influenced by caveolae. No report has ever examined the changes of caveolin in the process of CFs proliferation. In the present study, we examined the potential proliferation-inducing effect of AVP on adult rat CFs and the involvement of erk1/2 and the changes in the activation of erk1/2 in the presence of Sim. The role of caveolin1 (cav1) is also investigated. In addition, we further explored the mechanisms for the inhibitory effect of Sim on CFs proliferation, the effects of the changes in the abundance of cholesterol in the cell membrane on the expression of cav1 and the modulation of AVP-induced CFs proliferation by Sim. Our objectives are to elucidate further the mechanisms of cardiac remodeling during hypertension and further the understanding of the molecular mechanisms for statins in the prevention and treatment of cardiac remodeling, and to provide new theoretical evidences and prevention and treatment approaches for LVH of hypertension.
Methods In this study, adult rat CFs isolated from Sprague-Dawley (SD) rats were cultured and used as experimental model. We employed [~3H]-thymidine incorporation, flow cytometry, in vitro kinase assay, Western blot analysis and RT-PCR in the present study to investigate: (1) Effect of AVP on CFs proliferation, (2) Role of PKC and erk1/2 pathway in the proliferatory effect of AVP on CFs proliferation, (3) Effect of Sim on CFs proliferation, (4) Modulatory effect of Sim on PKC and erk1/2 pathway during CFs proliferation, (5) Changes of cav1 in the modulation of AVP-induced CFs proliferation by Sim, (6) Effect of exogenous cholesterol on the modulation of Sim on CFs proliferation and its relationship with cav1 expression.
Results (1) Treating cells with 10-9 ~ 10-6 mol/L AVP increased [~3H]-thymidine incorporation in a concentration-dependent manner. 10~(-7) mol/L and 10-6 mol/L AVP increased [~3H]-thymidine incorporation by (72.0±4.0)% and(158.0±19.1)%, respectively(P < 0.05). (2) The effect of AVP on [~3H]-thymidine incorporation was abolished by incubating adult rat CFs with V1 receptor antagonist, d(CH2)5[Tyr2(Me), Arg8]-vasopressin, but not V2 receptor antagonist, desglycinamide-[d(CH2)5, D-Ile2, Ile4, Arg8]-vasopressin. (3) Erk1/2 activation could be induced by AVP (0.1μmol/L). The activation peaked at 5 min, with subsequent decline to near baseline level at 2 hour after the initiation of the stimulation. (4) PD98059 abolished the mitogenic effect of AVP(P < 0.05). (5) Phorbol 12-myristate 13-acetate (PMA, 30 nmol/L), as well as AVP for 5 min activated erk1/2 phosphorylation as measured by Western blots(P<0.05). Depleting PKC by chronic PMA incubation (2.5μmol/L, 24 h) abolished the stimulating effect of AVP on erk1/2 phosphorylation(P < 0.05). (6) Calphostin C, a PKC inhibitor, markedly reduced [~3H]-thymidine incorporation upon 0.1μmol/L AVP stimulation(P < 0.05). (7) PKC activation could readily be induced by AVP (0.1μM). The activation peaked at 5 min (approx. 3-fold induction, P<0.05) and subsequently declined to near baseline level at 30 min after the initiation of AVP stimulation. (8) Ca2+ chelating agent BAPTA had no significant effect on DNA synthesis stimulated by AVP (P>0.05). (9) The protein level of p27Kip1 was markedly attenuated upon AVP treatment to (21.7±1.6)% of control level, while expression of cyclins D1, A and E increased to (5.7±0.5)-fold,(5.4±0.5)-fold and (6.0±0.7)-fold of control(P < 0.05). Inhibiting erk1/2 activation by PD98059 (30μmol/L) abolished the effect of AVP on protein expression of p27Kip1 as well as cyclins D1, E and A. (10) 0.1μmol/L AVP induced cell cycle progression from G0/G1 into S phase, accompanied by increased proliferation index (PI) (P<0.05). The effects of AVP on G0/G1-S phase progression and PI were inhibited by PD98059. (11) When pretreating cells with simvastatin (10-8 ~ 10-5 mol/L) for 24 h before 10~(-7) mol/L AVP stimulation for another 24 h, [~3H]-thymidine incorporation in adult rat CFs were (172.0±9.8)%, (151.3±7.7)%, (128.3±7.6)%, and (121.7±11.5)%, respectively, of control, all being significantly lower (P<0.05) than AVP single-drug treated cells, except in the 10-8 mol/L simvastatin treated group. (12) When pretreating cells with simvastatin (10-8 ~ 10-5 mol/L) for 24 h before 10~(-7) mol/L AVP stimulation for another 24 h, cells in S stage and PI tended to decrease, with those of 10~(-7) mol/L and 10-6 mol/L Sim groups being significantly lower (both P<0.05) than AVP single-drug treated cells. And PI was significantly lower (P<0.05) in 10~(-7) ~ 10-5 mol/L Sim cells than in AVP single-drug treated cells. (13) When pretreating cells with simvastatin (10-8 ~ 10-5 mol/L) for 24 h before 10~(-7) mol/L AVP stimulation for 5 min, erk1/2 activation reached (2.5±0.2)-fold, (1.9±0.1)-fold, (1.5±0.1)-fold, and(1.3±0.1)-fold, respectively, over control level, being significantly lower (P<0.05) in 10~(-7) ~ 10-5 mol/L Sim cells than in AVP single-drug treated cells. (14) When pretreating cells with simvastatin (10-8 ~ 10-5 mol/L) for 24 h before 10~(-7) mol/L AVP stimulation for 5 min, PKC activation reached (24.8±2.4)%, (21.5±2.6)%, (17.3±1.8)% and(15.0±1.3)%, respectively, of control level, being significantly lower (P<0.05) in 10-6 mol/L and 10-5 mol/L Sim cells than in AVP single-drug treated cells. (15) MVA pretreatment reversed the inhibitory effect of 10-6mol/L simvastatin on 10~(-7)mol/L AVP induced increase in [~3H]-thymidine incorporation and PKC and erk1/2 activation. (16) Geranylgeranyl pyrophosphate (GGPP) reversed the inhibitory effect of 10-6mol/L simvastatin on 10~(-7)mol/L AVP induced increase in [~3H]-thymidine incorporation and erk1/2 activation, whereas farnesyl pyrophosphate (FPP) had no significant effect. (17) 10~(-7) mol/L simvastatin significantly inhibited 10~(-7) mol/L AVP-induced increase in MBS-P expression(P<0.05). (18) Pretreating cells with 10μmol/L GGTI or 5μmol/L Y27632 for 24 h before 10~(-7) mol/L AVP stimulation for 5 min significantly inhibited the AVP-induced erk1/2 activation (P<0.05). (19) Cav1 antisense oligonucleotides significantly increased [~3H]-thymidine incorporation, PKC and erk1/2 activation and the expression of cyclins D1, A and E in CFs, and decreased the expression of p27kip1 (all P < 0.05). (20) The cav1 expression in CFs were (86.7±4.6)%, (79.0±8.6)%, (59.7±3.7)% and (46.0±3.1)% of control when treating cells with 10-9 ~ 10-6 mol/L AVP, with the expression levels in 10~(-7) mol/L and 10-6 mol/L AVP groups being significantly lower than that of control (P < 0.05). (21) When pretreating cells with simvastatin (10-8 ~ 10-5 mol/L) for 24 h before 10~(-7) mol/L AVP stimulation for 24 h, cav1 expression were (88.7±2.7)%, (70.3±2.6)%,(60.7±2.2)% and (56.3±1.9)% of AVP single-drug treated cells, respectively, being significantly lower (P<0.05) in 10~(-7) ~ 10-5 mol/L Sim cells than in AVP single-drug treated cells. The addition of 10-4 mol/L MVA to 10~(-7) mol/L AVP significantly increased cav1 expression (P < 0.05). (22) 10μg/ml, 20μg/ml and 30μg/ml cholesterol significantly increased cav1 expression in cells treated with 10-6mol/L simvastatin and 10~(-7)mol/L AVP (all P < 0.05). (23) When cells were incubated with 10% FBS, the addition of 20μg/ml cholesterol showed no apparent effect on cav1 protein expression (P > 0.05). However, when cells were incubated with 2% Methyl-β-cyclodextrin (MβCD), a maneuver to deplete cells of cholesterol, the restoration of cholesterol by MβCD-cholesterol complex (containing 20μg/ml cholesterol) caused a (2.7±0.2)-fold increase from the cholesterol-depleted condition (P < 0.05). (24) Exogenous cholesterol increased the cholesterol content in cells treated with 2% MβCD and 10-7 mol/L AVP combined with 10-6 mol/L simvastatin. Exogenous cholesterol also inhibited the increase in [3H]-thymidine incorporation upon 2% MβCD treatment, whereas it had little effects on cellular cholesterol and the increase in [3H]-thymidine incorporation when cells were treated with 10% FBS. (25) Erk1/2 activation was significantly attenuated when 20μg/ml cholesterol was added simultaneously with 10-6 mol/L simvastatin to 10-7 mol/L AVP treated cells when compared with AVP and simvastatin treated cells (P < 0.05).
Conclusions (1) AVP acts as a growth-factor for adult rat CFs. (2) The mitogenic effect of AVP is mediated via type 1 receptor and PKC–erk1/2 pathway. (3) AVP modulates the expression of cell cycle regulatory proteins p27Kip1 and cyclins D1, A and E, which lie down-stream of erk1/2 activation, and induces cell cycle progression of adult rat CFs. (4) Simvastatin inhibits AVP induced CFs proliferation, PKC and erk1/2 pathway activation, an effect that can be reversed by MVA. (5) Cav1 restoration by cholesterol enhances the inhibitory effect of simvastatin on AVP-induced CFs proliferation.
In summary, AVP can stimulate the proliferation of adult rat CFs via type 1 receptor and PKC–erk1/2 pathway, an effect can be inhibited by simvasatin. The inhibitory effect of simvastatin on AVP-induced CFs proliferation can be enhanced by exogenous cholesterol via the induction of cav1 exression.
引文
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