The E-domain region of mechano-growth factor inhibits cellular apoptosis and preserves cardiac function during myocardial infarction.
The E-domain region of mechano-growth factor inhibits cellular apoptosis and preserves cardiac function during myocardial infarction.
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DOI：
10.1007/s11010-013-1689-4
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发表时间：
2013-09
影响因子：
4.3
通讯作者：
Goldspink, Paul H.
中科院分区：
文献类型：
--
作者：
Mavrommatis, Evangelos;Shioura, Krystyna M.;Los, Tamara;Goldspink, Paul H.
胰岛素样生长因子-1 （IGF-1）异构体通过选择性剪接表达。次要亚型IGF-1Eb[也称为机械生长因子（MGF）]的表达对细胞应激有反应。由于IGF-1同种异构体在它们的e结构域区域不同，我们对确定MGF e结构域的生物学功能很感兴趣。为此，使用合成肽类似物来获得对e结构域作用的机制洞察。对H9c2细胞的处理表明，细胞摄取机制不涉及IGF-1受体激活，但导致核定位。多肽处理通过防止线粒体膜电位的崩溃和抑制caspase-3的激活，抑制山梨醇细胞应激下H9c2细胞的内在凋亡途径。因此，我们在小鼠心肌梗死（MI）时给予肽。心肌梗死后2周，检测基因表达和细胞死亡情况。根据PV环分析，未治疗小鼠的收缩和舒张功能明显下降。e肽的递送改善了功能的下降，并导致心脏收缩力的显著保存。与这些变化相关的是，心肌梗死后e肽处理小鼠活心肌的病理性肥大受到抑制，凋亡细胞核明显减少。我们得出结论，MGF e结构域肽的管理可能提供了一种调节局部组织IGF-1自分泌/旁分泌作用的方法，以保护心脏功能，防止细胞死亡和心脏的病理重塑。本文的在线版本（doi:10.1007/s11010-013-1689-4）包含补充资料，仅供授权用户使用。
Insulin-like growth factor-1 (IGF-1) isoforms are expressed via alternative splicing. Expression of the minor isoform IGF-1Eb [also known as mechano-growth factor (MGF)] is responsive to cell stress. Since IGF-1 isoforms differ in their E-domain regions, we are interested in determining the biological function of the MGF E-domain. To do so, a synthetic peptide analog was used to gain mechanistic insight into the actions of the E-domain. Treatment of H9c2 cells indicated a rapid cellular uptake mechanism that did not involve IGF-1 receptor activation but resulted in a nuclear localization. Peptide treatment inhibited the intrinsic apoptotic pathway in H9c2 cells subjected to cell stress with sorbitol by preventing the collapse of the mitochondrial membrane potential and inhibition of caspase-3 activation. Therefore, we administered the peptide at the time of myocardial infarction (MI) in mice. At 2 weeks post-MI cardiac function, gene expression and cell death were assayed. A significant decline in both systolic and diastolic function was evident in untreated mice based on PV loop analysis. Delivery of the E-peptide ameliorated the decline in function and resulted in significant preservation of cardiac contractility. Associated with these changes were an inhibition of pathologic hypertrophy and significantly fewer apoptotic nuclei in the viable myocardium of E-peptide-treated mice post-MI. We conclude that administration of the MGF E-domain peptide may provide a means of modulating local tissue IGF-1 autocrine/paracrine actions to preserve cardiac function, prevent cell death, and pathologic remodeling in the heart. The online version of this article (doi:10.1007/s11010-013-1689-4) contains supplementary material, which is available to authorized users.
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影响因子：
3.3
作者：
Barton, Elisabeth R.;DeMeo, J.;Lei, Hanqin
通讯作者：
Lei, Hanqin
影响因子：
20.1
作者：
Morrison, LE;Hoover, HE;Glembotski, CC
通讯作者：
Glembotski, CC
影响因子：
4
作者：
Matthews, KG;Devlin, GP;Bass, JJ
通讯作者：
Bass, JJ
影响因子：
--
作者：
Colao, A
通讯作者：
Colao, A
影响因子：
5.6
作者：
MUTA, K;KRANTZ, SB
通讯作者：
KRANTZ, SB