CN103285380A - 胰岛素心肌保护中的新应用 - Google Patents

胰岛素心肌保护中的新应用 Download PDF

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CN103285380A
CN103285380A CN 201210382244 CN201210382244A CN103285380A CN 103285380 A CN103285380 A CN 103285380A CN 201210382244 CN201210382244 CN 201210382244 CN 201210382244 A CN201210382244 A CN 201210382244A CN 103285380 A CN103285380 A CN 103285380A
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insulin
phlpp
akt
myocardial
ischemia
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马恒
邢媛
高峰
余璐
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Fourth Military Medical University FMMU
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Fourth Military Medical University FMMU
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Abstract

本发明涉及胰岛素调节蛋白磷酸酶PHLPP-1,强化胰岛素用于改善心肌缺血损伤中的用途的新认识。胰岛素激活蛋白激酶B(Akt)-内皮型一氧化氮合酶(eNOS)信号途径是重要的心肌保护机制;衰老导致心肌胰岛素-Akt保护作用衰退,但机制尚未阐明。新报道的蛋白磷酸酶PHLPP-1特异性使Akt去磷酸化失活,抑制Akt的心肌保护作用。我们的研究首次发现①成年心肌中,胰岛素通过抑制PHLPP-1“强化”Akt活性;②而衰老状态下,PHLPP-1高表达削弱胰岛素保护作用导致衰老心肌缺血易损性;③胰岛素通过对PHLPP-1蛋白泛素化降解通路的调节下调PHLPP-1蛋白表达。基于上述发现,本发明围绕胰岛素对PHLPP-1的调节作用,首次提出胰岛素发挥心肌保护作用的新机制,并为防治老年性心血管疾病提供新思路。

Description

胰岛素心肌保护中的新应用
近年来,缺血性心脏病(IHD)严重威胁国人健康。虽然,冠状动脉内溶栓及冠脉搭桥等内外科治疗手段已被广泛应用,但是继之出现的再灌注损伤日益受到心脏病学家的高度重视。针对缺血再灌注导致的心肌损伤,已有研究证实胰岛素可作为外源药物激活血管内皮细胞蛋白激酶B(Akt)-内皮型一氧化氮合酶(eNOS)使一氧化氮(NO)生成增加,抑制缺血再灌注引起的冠脉血管内皮细胞凋亡,改善心肌灌注,进而有效促进缺血心脏的功能恢复,因此胰岛素激活Akt-eNOS信号途径是重要的心肌内源性保护机制。衰老导致心肌出现易损状态,显著降低心脏抵抗缺血/再灌注损伤的耐受力,研究发现这与心肌内源性保护能力降低密切相关。但是,衰老导致心肌Akt-eNOS活性下降,削弱胰岛素细胞保护作用的具体机制至今仍不清楚。有研究已证实蛋白磷酸酶的去磷酸化作用可能是心肌保护性蛋白激酶失活的原因,新近的研究报道,蛋白磷酸酶PHLPP-1可特异性导致Akt去磷酸化失活,抑制心肌细胞的存活,但是,PHLPP-1是否参与了心肌胰岛素-Akt-eNOS保护能力衰退,进而导致衰老心肌的缺血易损性尚不清楚。
相比较已有研究关于胰岛素发挥心肌保护方式,本发明明确了心肌中胰岛素对蛋白磷酸酶PHLPP-1有调节作用,即胰岛素通过抑制缺血再灌注中PHLPP-1的蛋白水平的上调,完善其心肌保护作用机制,进而明确了衰老心肌缺血易损性以及对胰岛素作用反应性降低的机制。
本发明明确了心肌中胰岛素对PHLPP-1的调节作用。
本发明的目的是通过下述技术方案实现:
1胰岛素预防和治疗心肌缺血/再灌注损伤的新应用现有的研究已表明胰岛素---蛋白激酶B(Akt)---内皮型一氧化氮合酶(eNOS)作为重要的内源性保护机制可有效抑制缺血再灌注心肌细胞和冠脉内皮细胞凋亡,改善冠脉血管舒张功能和心肌灌注,并最终促进血管和缺血心脏功能的恢复。本发明区别于已有研究的特是:胰岛素通过抑制缺血再灌注中PHLPP-1的表达,降低Akt的去磷酸化,保护缺血心脏。
2根据权利要求1所述的胰岛素的新作用,其特征在于再灌注期给予胰岛素处理可显著抑制缺血/再灌注心肌PHLPP-1蛋白水平,同时,显著提高Akt473位点丝氨酸的磷酸化,提高Akt活性,强化胰岛素对缺血心脏的保护作用。
3根据权利要求2中所述的胰岛素的新作用,其特征在于胰岛素可调节PHLPP-1的蛋白泛素化作用,最终下调PHLPP-1蛋白水平,强化胰岛素对Akt的磷酸化激活,促进心肌细胞生存,保护缺血心脏。
4根据权利要求2所述的胰岛素的新作用,在衰老条件下,心肌PHLPP-1蛋白水平上调,此时,心肌对胰岛素的反应性减弱,即PHLPP-1高表达削弱胰岛素保护作用致使衰老心肌缺血易损性。
本发明有益效果是:本发明提示成年心肌中胰岛素抑制PHLPP-1强化Akt对缺血心脏的保护新机制;而衰老心肌胰岛素抵抗,并且老年心肌PHLPP-1表达增加,后者进一步“恶化”胰岛素的细胞保护效应,PHLPP-1的异常高表达和胰岛素-Akt信号的异常不敏感,导致老年心肌缺血易损状态。
具体实施方式:
1在整体动物研究胰岛素对缺血心肌PHLPP-1和Akt信号之间的作用及其保护效应:采用成年C57小鼠(3M)建立整体小鼠心肌缺血再灌注模型,再灌注期予胰岛素,超声监测心脏功能。检测心脏结构以及胰岛素敏感性。测定心肌PHLPP-1表达水平和p-Akt水平,并检测缺血再灌注导致的心肌细胞凋亡和心肌梗死面积。
2在衰老动物整体水平,研究胰岛素对缺血心肌PHLPP-1和Akt信号之间的作用及其保护效应:采用老年C57小鼠(20-22M),以成年小鼠(3-4M)为对照,建立整体心肌缺血再灌注模型,再灌注期予胰岛素处理。明确心脏损伤程度的机能和形态学指标以及胰岛素敏感性,阐明老年心肌PHLPP-1表达水平和胰岛素处理以及p-Akt水平之间的动态关系。

Claims (4)

1.胰岛素预防和治疗心肌缺血/再灌注损伤的新应用现有的研究已表明胰岛素---蛋白激酶B(Akt)---内皮型一氧化氮合酶(eNOS)作为重要的内源性保护机制可有效抑制缺血再灌注心肌细胞和冠脉内皮细胞凋亡,改善冠脉血管舒张功能和心肌灌注,并最终促进血管和缺血心脏功能的恢复。本发明区别于已有研究的特点是:胰岛素通过抑制缺血再灌注中PHLPP-1的表达,降低Akt的去磷酸化,保护缺血心脏。
2.根据权利要求1所述的胰岛素的新作用,其特征在于再灌注期给予胰岛素处理可显著抑制缺血/再灌注心肌PHLPP-1蛋白水平,同时,显著提高Akt 473位点丝氨酸的磷酸化,提高Akt活性,强化胰岛素对缺血心脏的保护作用。
3.根据权利要求2中所述的胰岛素的新作用,其特征在于胰岛素可调节PHLPP-1的蛋白泛素化作用,最终下调PHLPP-1蛋白水平,强化胰岛素对Akt的磷酸化激活,促进心肌细胞生存,保护缺血心脏。
4.根据权利要求2所述的胰岛素的新作用,在衰老条件下,心肌PHLPP-1蛋白水平上调,此时,心肌对胰岛素的反应性减弱,即PHLPP-1高表达削弱胰岛素保护作用致使衰老心肌缺血易损性。
CN 201210382244 2012-10-10 2012-10-10 胰岛素心肌保护中的新应用 Pending CN103285380A (zh)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11260105B2 (en) 2015-11-06 2022-03-01 The Board Of Trustees Of The University Of Illinois Peptides and method for treatment of cardiac arrest

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11260105B2 (en) 2015-11-06 2022-03-01 The Board Of Trustees Of The University Of Illinois Peptides and method for treatment of cardiac arrest

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Application publication date: 20130911