ACE2-Ang(1-7)-Mas轴介导的胰岛内皮功能对β细胞功能的调节及机制
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摘要
目的：以血管紧张素转换酶2(ACE2)基因敲除小鼠为实验对象，探讨ACE2-Ang(1-7)-Mas轴对长期高脂喂养小鼠胰岛微循环及β细胞功能的影响。
方法：野生型C57小鼠(WT)及ACE2基因敲除(KO)小鼠均分为普通饮食(WT， KO)和高脂饮食(WH，KH)两组，16周后,对四组小鼠行葡萄糖耐量实验(IPGTT)及葡萄糖刺激后胰岛素释放实验(IPIRT)检测胰岛功能，行胰岛素耐量实验(IPITT)检测外周组织胰岛素敏感性，以免疫组化法检测胰岛细胞内胰岛素相对含量(IRC)，胰岛素阳性细胞密度(ICD),以胰岛内CD31染色检测胰岛内微血管密度(MVD)，TUNEL法检测胰岛内细胞凋亡水平。胶原酶法分离四组小鼠胰岛细胞并进行体外静态培养，以硝酸还原酶法检测上清NO水平，以RT-PCR法检测胰岛组织内eNOS,ICAM-1，VCAM-1mRNA的相对表达量。
结果：正常饮食条件下，与WT组相比，KO组IPGTT葡萄糖曲线下面积(AUCG)无明显差异，葡萄糖刺激后第一时相胰岛素分泌呈下降趋势,胰岛组织内胰岛素相对含量(IRC)、胰岛素阳性细胞核密度(ICD)略减低，胰岛组织内微血管密度(MVD)也有减少趋势，但均未达到统计学差异。高脂饮食条件下，WH组较WT组IPGTT葡萄糖曲线下面积(AUCG)显著增加（P<0.05)，葡萄糖刺激后第一时相胰岛素分泌减少,胰岛内胰岛素相对含量(IRC)下降（P<0.05)，胰岛组织内单位面积TUNEL阳性细胞数增加（P<0.05)。而与WH组相比，KH组IPGTT葡萄糖曲线下面积(AUCG)进一步上升（P<0.05)，葡萄糖刺激后第一时相胰岛素分泌显著减少（P<0.05)，胰岛内胰岛素相对含量(IRC)、胰岛组织内微血管密度(MVD)明显下降（P<0.05)，胰岛组织内单位面积TUNEL阳性细胞数显著增加（P<0.05)。WT组与KO组胰岛内皮细胞NO合成释放无显著差异，与WT组相比，WH组胰岛内皮细胞NO含量降低（P<0.05)，KH组较WH组胰岛内皮细胞NO进一步下降（P<0.05)。与WT组相比，KO组胰岛组织eNOS mRNA的相对表达量呈下降趋势，但未达到统计学差异，ICAM-1及VCAM-1mRNA的相对表达量无明显差异。WH组较WT组胰岛组织内ICAM-1，VCAM-1mRNA的相对表达量增加（P<0.05)，eNOSmRNA的相对表达量下降（P<0.05)。 KH组胰岛组织内ICAM-1（P<0.05)，VCAM-1mRNA（P<0.05)的相对表达量较WH组进一步上升，eNOSmRNA的相对表达量显著下降（P<0.05)。
结论：ACE2基因敲除加重长期高脂诱导小鼠胰岛内皮功能损伤、糖代谢异常及胰岛β细胞功能障碍。
目的：探讨Mas下调对胰岛微血管内皮细胞（MS-1）脂性凋亡的影响及其对β细胞的调节效应。
方法：利用小干扰RNA(siRNA)下调MS-1细胞Mas受体的表达，棕榈酸(PA)干预24h后，分别对四组细胞（MS-1，MS-1siRNA,MS-1PA, MS-1siRNA+PA）以流式检测细胞凋亡率，以Western blot法检测Akt-eNOS信号通路、JNK、p38磷酸化水平及bcl-2,bax,caspase3蛋白水平的表达，以RT-PCR法检测FoxO1, p22phox，TNF-mRNA的表达，以硝酸酶还原法法检测上清中NO水平。用siRNA及棕榈酸(PA)干预获得不同功能状态的MS-1细胞，并与小鼠胰岛β细胞（MIN6）共培养，以GSIS法检测MIN6细胞的胰岛素分泌功能。
结果：siRNA转染体外培养的MS-1细胞，可以显著降低MS-1细胞Mas mRNA的表达。与MS-1组相比，MS-1siRNA组细胞凋亡率无差异；p-Akt,p-eNOS,p-JNK,p-p38,及caspase3蛋白表达水平及bax/bcl-2无差别；TNF-mRNA的表达呈上升趋势，但未达到统计学差异；FoxO1, p22phox mRNA的表达无明显差异；上清中NO水平呈下降趋势，但未达到统计学差异。与MS-1组相比，MS-1PA及MS-1siRNA+PA组细胞凋亡率显著上升；p-Akt,p-eNOS蛋白表达下降；bax/bcl-2,p-JNK,p-p38,及caspase3蛋白表达明显上升；TNF-，p22phox mRNA的表达增加；上清NO水平下降。FoxO1mRNA的表达无差异。与MS-1PA相比，MS-1siRNA+PA组细胞凋亡率进一步增加，p-Akt,p-eNOS下降， bax/bcl-2,caspase3蛋白及TNF-mRNA表达增加，p-p38，p-JNK蛋白表达及p22phox，FoxO1mRNA的表达无差异，上清NO水平下降。MIN6-MS-1组与MIN6-MS-1siRNA组基础胰岛素及GSIS均无差异。MIN6-MS-1PA组和MIN6-MS-1siRNA+PA组基础胰岛素分泌分别较MIN6-MS-1组和MIN6-MS-1siRNA组呈下降趋势，但均未达到统计学差异。MIN6-MS-1PA组与MIN6-MS-1siRNA+PA组GSIS较MIN6-MS-1组和MIN6-MS-1siRNA组均明显下降(均P＜0.05)。MIN6-MS-1siRNA+PA组较MIN6-MS-1PA组GSIS呈下降趋势，但未达到统计学差异(P＞0.05)。
结论：Mas沉默通过下调Akt-eNOS信号通路，加重PA诱导的胰岛微动脉内皮细胞的凋亡，促进了PA诱导的内皮细胞功能障碍，进而导致胰岛β细胞功能受损。
Objective The aim of this study was to evaluate the effects of Angiotensin-convertingenzyme2(ACE2) on glucose homeostasis and islet function in mice.Methods Male wildtype (WT) and ACE2knockout (ACE2KO) mice were divided intochow diet group and long-term high-fat diet (HFD) group for16weeks.
（1）Islet function of the animals was evaluated by intraperitoneal glucose tolerance test(IPGTT) and intraperitoneal insulin releasing test (IPIRT). The insulin sensitivity waspresented by intraperitoneal insulin tolerance test (IPITT).
（2）The pancreas was immunohistochemically stained to analyze the relative content ofinsulin (IRC), insulin-positive cell density (ICD), microvessel density (MVD) in islets. Theapoptosis of islet was evaluated by TUNEL.
（3）Pancreatic islets isolated by handpicking following collagenase digestion. NOproduction was detected by nitrate reductase assay. Insulin levels were measured with themouse insulin ELISA kit.
（4）The eNOS, ICAM-1, VCAM-1mRNA in islet were observed by RT-PCR.
Results
（1）There was no significant difference of AUCG between WT mice and KO mice. TheAUCG in WH mice was significantly elevated than that in WT mice (p＜0.05). The AUCGin KH group was obviously increased than that in KO (p＜0.05). Compared with WH mice,increased AUCG in KH mice was observed (p＜0.05).
（2）The AUCI0-30and AUCI0-5were not different between WT and KO group. Decrease AUCI0-5and increased AUCI0-30were observed in WH group compared with those in WTgroup (both p＜0.05). The AUCI0-30in KH group was not increased when compared withthat in KO group.
（3）In IPITT, similar glucose disappearance rate was observed in WT and KO mice as wellas between KH and WH mice.
（4）The IRC, ICD, MVD and NO concentration of islet were slightly decreased in KOmice than those in WT mice, but the difference was not significant. Decreased IRC,NOconcentration and increased apoptosis in islet were noted in WH group in comparison withWT group (p＜0.05). In comparison with WH mice, KH mice exhibited a decreasedIRC,MVD,NO concentration and increased apoptosis in islet (p＜0.05).
（5）The expression of eNOS, ICAM-1and VCAM-1between WT and KO mice was notsignificant. WH mice exhibited increased ICAM-1，VCAM-1expression and decreasedeNOS expression (all P<0.05). In comparison with WH mice, reduced eNOS and increasedICAM-1and VCAM-1were observed in KH mice (all P<0.05).
Conclusions Loss of ACE2deteriorates impairment of islet β cell function and pancreaticislet endothelial function in mice with long-term high-fat diet.
Objective The aim of this study was to evaluate the apoptosis effects of palmitate on MS-1cells. Examine the role of Mas on lipoapoptosis of MS-1cells.
Methods（1）We down-regulated Mas expression by siRNA in mice islet microvessel cellsMS-1. After transfected with Mas-siRNA, Mas mRNA expression was detected byreal-time quantitative reverse transcription-polymerase chain reaction (RT-PCR).（2）Culturing the MS-1cells which were transfected by Mas-siRNA at125uMconcerntration of PA for24h. MS-1cells apoptosis was analyzed by Annexin V-FITC/PIflow cytometry. MS-1cells which were induced by siRNA and/or PA was co-cultured withMIN6for24h. Glucose-stimulated insulin secretion (GSIS) in MIN6was examined afterco-culturing.（3）Akt-eNOS, JNK, p38-MAPK signaling pathways activation and bcl-2, bax, caspase-3expression in MS-1cells were observed by Western-blotting.（4）NO production from MS-1cells was detected by nitrate reductase assay.（5）The FoxO1, p22phox，TNF-mRNA in MS-1cells were detected by RT-PCR.
Results （1）Mas mRNA expression in Mas-siRNA transfected MS-1cells showed amarked reduction, compared with the negative control.(p＜0.05).（2）No significant difference of the percentage of apoptosis cell were indicated betweennormal MS-1cells and Mas-siRNA transfected MS-1cells. PA induced the MS-1cellsapoptosis (p＜0.05). The cell apoptosis rates induced by PA increased after beingtransfected by Mas-siRNA (p＜0.05).（3）PA promoted the expression of p-JNK, p-p38, caspase-3,Bax and inhibited theexpression of p-Akt, p-eNOS, bcl-2in MS-1cells (all p＜0.05). The up-regulation ofcaspase-3,Bax and down-regulation of p-Akt,p-eNOS, bcl-2were greater after Mas-siRNA transfection (all p＜0.05).（4）There was no difference of NO concentration between MS-1cells with and withoutMas-siRNA transfection. PA reduced the NO concentrations in MS-1cells (both p＜0.05).After transfected by Mas-siRNA, the reduction of NO concentration induced by PA wasgreater (p＜0.05).（5）The expression of FoxO1mRNAwas not significant among different MS-1cells. Thep22phox，TNF-mRNA expression were not significant between MS-1cells with andwithout Mas-siRNA transfection. PA stimulated p22phox，TNF-mRNA expression inMS-1cells (all p＜0.05). The p22phox mRNA expression between MS-1cells with andwithout Mas-siRNA transfection induced by PA was not significant. TransfectionMas-siRNA markedly increased the TNF-mRNA expression in MS-1cells induced by PA(P<0.05).（6）After co-cultured, the basic insulin among four group was not significant. The GSIS inMIN6cells co-cultured with MS-1cells with and without Mas-siRNA was not different. Incomparison with MIN6cells co-cultured with MS-1which was not stimulated by PA, theMIN6cells co-cultured with MS-1cells induced by PA exhibited a reduction of GSIS (bothp＜0.05). With the intervention by PA, the MIN6cells co-cultured with MS-1cellstransfected by Mas-siRNA showed a slightly reduced GSIS compared with the MIN6cellsco-cultured with normal MS-1cells,but the difference was not significant (P＞0.05).
Conclusions Mas-siRNA transfection promoted MS-1cells lipoapoptosis induced by PAthrough down-regulation of Akt-eNOS signaling pathways, bcl-2expression andup-regulation of caspase-3, bax expression.
方法：野生型C57小鼠(WT)及ACE2基因敲除(KO)小鼠均分为普通饮食(WT， KO)和高脂饮食(WH，KH)两组，16周后,对四组小鼠行葡萄糖耐量实验(IPGTT)及葡萄糖刺激后胰岛素释放实验(IPIRT)检测胰岛功能，行胰岛素耐量实验(IPITT)检测外周组织胰岛素敏感性，以免疫组化法检测胰岛细胞内胰岛素相对含量(IRC)，胰岛素阳性细胞密度(ICD),以胰岛内CD31染色检测胰岛内微血管密度(MVD)，TUNEL法检测胰岛内细胞凋亡水平。胶原酶法分离四组小鼠胰岛细胞并进行体外静态培养，以硝酸还原酶法检测上清NO水平，以RT-PCR法检测胰岛组织内eNOS,ICAM-1，VCAM-1mRNA的相对表达量。
结果：正常饮食条件下，与WT组相比，KO组IPGTT葡萄糖曲线下面积(AUCG)无明显差异，葡萄糖刺激后第一时相胰岛素分泌呈下降趋势,胰岛组织内胰岛素相对含量(IRC)、胰岛素阳性细胞核密度(ICD)略减低，胰岛组织内微血管密度(MVD)也有减少趋势，但均未达到统计学差异。高脂饮食条件下，WH组较WT组IPGTT葡萄糖曲线下面积(AUCG)显著增加（P<0.05)，葡萄糖刺激后第一时相胰岛素分泌减少,胰岛内胰岛素相对含量(IRC)下降（P<0.05)，胰岛组织内单位面积TUNEL阳性细胞数增加（P<0.05)。而与WH组相比，KH组IPGTT葡萄糖曲线下面积(AUCG)进一步上升（P<0.05)，葡萄糖刺激后第一时相胰岛素分泌显著减少（P<0.05)，胰岛内胰岛素相对含量(IRC)、胰岛组织内微血管密度(MVD)明显下降（P<0.05)，胰岛组织内单位面积TUNEL阳性细胞数显著增加（P<0.05)。WT组与KO组胰岛内皮细胞NO合成释放无显著差异，与WT组相比，WH组胰岛内皮细胞NO含量降低（P<0.05)，KH组较WH组胰岛内皮细胞NO进一步下降（P<0.05)。与WT组相比，KO组胰岛组织eNOS mRNA的相对表达量呈下降趋势，但未达到统计学差异，ICAM-1及VCAM-1mRNA的相对表达量无明显差异。WH组较WT组胰岛组织内ICAM-1，VCAM-1mRNA的相对表达量增加（P<0.05)，eNOSmRNA的相对表达量下降（P<0.05)。 KH组胰岛组织内ICAM-1（P<0.05)，VCAM-1mRNA（P<0.05)的相对表达量较WH组进一步上升，eNOSmRNA的相对表达量显著下降（P<0.05)。
结论：ACE2基因敲除加重长期高脂诱导小鼠胰岛内皮功能损伤、糖代谢异常及胰岛β细胞功能障碍。
目的：探讨Mas下调对胰岛微血管内皮细胞（MS-1）脂性凋亡的影响及其对β细胞的调节效应。
方法：利用小干扰RNA(siRNA)下调MS-1细胞Mas受体的表达，棕榈酸(PA)干预24h后，分别对四组细胞（MS-1，MS-1siRNA,MS-1PA, MS-1siRNA+PA）以流式检测细胞凋亡率，以Western blot法检测Akt-eNOS信号通路、JNK、p38磷酸化水平及bcl-2,bax,caspase3蛋白水平的表达，以RT-PCR法检测FoxO1, p22phox，TNF-mRNA的表达，以硝酸酶还原法法检测上清中NO水平。用siRNA及棕榈酸(PA)干预获得不同功能状态的MS-1细胞，并与小鼠胰岛β细胞（MIN6）共培养，以GSIS法检测MIN6细胞的胰岛素分泌功能。
结果：siRNA转染体外培养的MS-1细胞，可以显著降低MS-1细胞Mas mRNA的表达。与MS-1组相比，MS-1siRNA组细胞凋亡率无差异；p-Akt,p-eNOS,p-JNK,p-p38,及caspase3蛋白表达水平及bax/bcl-2无差别；TNF-mRNA的表达呈上升趋势，但未达到统计学差异；FoxO1, p22phox mRNA的表达无明显差异；上清中NO水平呈下降趋势，但未达到统计学差异。与MS-1组相比，MS-1PA及MS-1siRNA+PA组细胞凋亡率显著上升；p-Akt,p-eNOS蛋白表达下降；bax/bcl-2,p-JNK,p-p38,及caspase3蛋白表达明显上升；TNF-，p22phox mRNA的表达增加；上清NO水平下降。FoxO1mRNA的表达无差异。与MS-1PA相比，MS-1siRNA+PA组细胞凋亡率进一步增加，p-Akt,p-eNOS下降， bax/bcl-2,caspase3蛋白及TNF-mRNA表达增加，p-p38，p-JNK蛋白表达及p22phox，FoxO1mRNA的表达无差异，上清NO水平下降。MIN6-MS-1组与MIN6-MS-1siRNA组基础胰岛素及GSIS均无差异。MIN6-MS-1PA组和MIN6-MS-1siRNA+PA组基础胰岛素分泌分别较MIN6-MS-1组和MIN6-MS-1siRNA组呈下降趋势，但均未达到统计学差异。MIN6-MS-1PA组与MIN6-MS-1siRNA+PA组GSIS较MIN6-MS-1组和MIN6-MS-1siRNA组均明显下降(均P＜0.05)。MIN6-MS-1siRNA+PA组较MIN6-MS-1PA组GSIS呈下降趋势，但未达到统计学差异(P＞0.05)。
结论：Mas沉默通过下调Akt-eNOS信号通路，加重PA诱导的胰岛微动脉内皮细胞的凋亡，促进了PA诱导的内皮细胞功能障碍，进而导致胰岛β细胞功能受损。
Objective The aim of this study was to evaluate the effects of Angiotensin-convertingenzyme2(ACE2) on glucose homeostasis and islet function in mice.Methods Male wildtype (WT) and ACE2knockout (ACE2KO) mice were divided intochow diet group and long-term high-fat diet (HFD) group for16weeks.
（1）Islet function of the animals was evaluated by intraperitoneal glucose tolerance test(IPGTT) and intraperitoneal insulin releasing test (IPIRT). The insulin sensitivity waspresented by intraperitoneal insulin tolerance test (IPITT).
（2）The pancreas was immunohistochemically stained to analyze the relative content ofinsulin (IRC), insulin-positive cell density (ICD), microvessel density (MVD) in islets. Theapoptosis of islet was evaluated by TUNEL.
（3）Pancreatic islets isolated by handpicking following collagenase digestion. NOproduction was detected by nitrate reductase assay. Insulin levels were measured with themouse insulin ELISA kit.
（4）The eNOS, ICAM-1, VCAM-1mRNA in islet were observed by RT-PCR.
Results
（1）There was no significant difference of AUCG between WT mice and KO mice. TheAUCG in WH mice was significantly elevated than that in WT mice (p＜0.05). The AUCGin KH group was obviously increased than that in KO (p＜0.05). Compared with WH mice,increased AUCG in KH mice was observed (p＜0.05).
（2）The AUCI0-30and AUCI0-5were not different between WT and KO group. Decrease AUCI0-5and increased AUCI0-30were observed in WH group compared with those in WTgroup (both p＜0.05). The AUCI0-30in KH group was not increased when compared withthat in KO group.
（3）In IPITT, similar glucose disappearance rate was observed in WT and KO mice as wellas between KH and WH mice.
（4）The IRC, ICD, MVD and NO concentration of islet were slightly decreased in KOmice than those in WT mice, but the difference was not significant. Decreased IRC,NOconcentration and increased apoptosis in islet were noted in WH group in comparison withWT group (p＜0.05). In comparison with WH mice, KH mice exhibited a decreasedIRC,MVD,NO concentration and increased apoptosis in islet (p＜0.05).
（5）The expression of eNOS, ICAM-1and VCAM-1between WT and KO mice was notsignificant. WH mice exhibited increased ICAM-1，VCAM-1expression and decreasedeNOS expression (all P<0.05). In comparison with WH mice, reduced eNOS and increasedICAM-1and VCAM-1were observed in KH mice (all P<0.05).
Conclusions Loss of ACE2deteriorates impairment of islet β cell function and pancreaticislet endothelial function in mice with long-term high-fat diet.
Objective The aim of this study was to evaluate the apoptosis effects of palmitate on MS-1cells. Examine the role of Mas on lipoapoptosis of MS-1cells.
Methods（1）We down-regulated Mas expression by siRNA in mice islet microvessel cellsMS-1. After transfected with Mas-siRNA, Mas mRNA expression was detected byreal-time quantitative reverse transcription-polymerase chain reaction (RT-PCR).（2）Culturing the MS-1cells which were transfected by Mas-siRNA at125uMconcerntration of PA for24h. MS-1cells apoptosis was analyzed by Annexin V-FITC/PIflow cytometry. MS-1cells which were induced by siRNA and/or PA was co-cultured withMIN6for24h. Glucose-stimulated insulin secretion (GSIS) in MIN6was examined afterco-culturing.（3）Akt-eNOS, JNK, p38-MAPK signaling pathways activation and bcl-2, bax, caspase-3expression in MS-1cells were observed by Western-blotting.（4）NO production from MS-1cells was detected by nitrate reductase assay.（5）The FoxO1, p22phox，TNF-mRNA in MS-1cells were detected by RT-PCR.
Results （1）Mas mRNA expression in Mas-siRNA transfected MS-1cells showed amarked reduction, compared with the negative control.(p＜0.05).（2）No significant difference of the percentage of apoptosis cell were indicated betweennormal MS-1cells and Mas-siRNA transfected MS-1cells. PA induced the MS-1cellsapoptosis (p＜0.05). The cell apoptosis rates induced by PA increased after beingtransfected by Mas-siRNA (p＜0.05).（3）PA promoted the expression of p-JNK, p-p38, caspase-3,Bax and inhibited theexpression of p-Akt, p-eNOS, bcl-2in MS-1cells (all p＜0.05). The up-regulation ofcaspase-3,Bax and down-regulation of p-Akt,p-eNOS, bcl-2were greater after Mas-siRNA transfection (all p＜0.05).（4）There was no difference of NO concentration between MS-1cells with and withoutMas-siRNA transfection. PA reduced the NO concentrations in MS-1cells (both p＜0.05).After transfected by Mas-siRNA, the reduction of NO concentration induced by PA wasgreater (p＜0.05).（5）The expression of FoxO1mRNAwas not significant among different MS-1cells. Thep22phox，TNF-mRNA expression were not significant between MS-1cells with andwithout Mas-siRNA transfection. PA stimulated p22phox，TNF-mRNA expression inMS-1cells (all p＜0.05). The p22phox mRNA expression between MS-1cells with andwithout Mas-siRNA transfection induced by PA was not significant. TransfectionMas-siRNA markedly increased the TNF-mRNA expression in MS-1cells induced by PA(P<0.05).（6）After co-cultured, the basic insulin among four group was not significant. The GSIS inMIN6cells co-cultured with MS-1cells with and without Mas-siRNA was not different. Incomparison with MIN6cells co-cultured with MS-1which was not stimulated by PA, theMIN6cells co-cultured with MS-1cells induced by PA exhibited a reduction of GSIS (bothp＜0.05). With the intervention by PA, the MIN6cells co-cultured with MS-1cellstransfected by Mas-siRNA showed a slightly reduced GSIS compared with the MIN6cellsco-cultured with normal MS-1cells,but the difference was not significant (P＞0.05).
Conclusions Mas-siRNA transfection promoted MS-1cells lipoapoptosis induced by PAthrough down-regulation of Akt-eNOS signaling pathways, bcl-2expression andup-regulation of caspase-3, bax expression.
引文
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