Short term doxycycline treatment induces sustained improvement in myocardial infarction border zone contractility.
Short term doxycycline treatment induces sustained improvement in myocardial infarction border zone contractility.
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DOI：
10.1371/journal.pone.0192720
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Ratcliffe MB
中科院分区：
文献类型：
--
作者：
Spaulding K;Takaba K;Collins A;Faraji F;Wang G;Aguayo E;Ge L;Saloner D;Wallace AW;Baker AJ;Lovett DH;Ratcliffe MB
心肌梗死周围非缺血性边缘区收缩力降低部分是由于细胞内基质金属蛋白酶-2（MMP-2）降解心肌细胞肌节成分所致。我们最近报道，心肌梗死后边缘区的MMP-2水平增加，并且心肌梗死后两周使用强力霉素治疗与MMP-2水平正常化以及离体收缩蛋白在心肌边缘区产生力量的改善有关。本研究的目的是确定是否有一个持续的影响，短期治疗与强力霉素（Dox）的边缘区功能在一个大型动物模型的前心尖心肌梗死（MI）。在14只绵羊中建立了前尖部MI。7只绵羊接受多西环素0.8 mg/kg/hr IV给药2周。心肌梗死前2周、梗死后2周和6周分别行心脏MRI检查。6周时，2只绵羊在MRI前因手术/麻醉相关原因死亡。其余12只绵羊完成了方案。Western blot检测强力霉素诱导细胞内MMP-2表达持续下降（3649±643 MI+Dox vs 9236±114 MI相对强度; p = 0.0009），离体收缩性改善（65.3±2.0 MI+Dox vs 39.7±0.8 MI mN/mm 2; p<0.0001）和收缩末期离梗死边缘1.0 cm处的心室壁厚度增加（12.4±0.6 MI+Dox vs 10.0±0.5 MI mm; p = 0.0095）。在有限的两周时间内给予多西环素与离体收缩力的持续改善和MI后六周边界区收缩末期壁厚度的增加相关。这些发现与细胞内MMP-2活性的降低有关。
Decreased contractility in the non-ischemic border zone surrounding a MI is in part due to degradation of cardiomyocyte sarcomeric components by intracellular matrix metalloproteinase-2 (MMP-2). We recently reported that MMP-2 levels were increased in the border zone after a MI and that treatment with doxycycline for two weeks after MI was associated with normalization of MMP-2 levels and improvement in ex-vivo contractile protein developed force in the myocardial border zone. The purpose of the current study was to determine if there is a sustained effect of short term treatment with doxycycline (Dox) on border zone function in a large animal model of antero-apical myocardial infarction (MI). Antero-apical MI was created in 14 sheep. Seven sheep received doxycycline 0.8 mg/kg/hr IV for two weeks. Cardiac MRI was performed two weeks before, and then two and six weeks after MI. Two sheep died prior to MRI at six weeks from surgical/anesthesia-related causes. The remaining 12 sheep completed the protocol. Doxycycline induced a sustained reduction in intracellular MMP-2 by Western blot (3649±643 MI+Dox vs 9236±114 MI relative intensity; p = 0.0009), an improvement in ex-vivo contractility (65.3±2.0 MI+Dox vs 39.7±0.8 MI mN/mm2; p<0.0001) and an increase in ventricular wall thickness at end-systole 1.0 cm from the infarct edge (12.4±0.6 MI+Dox vs 10.0±0.5 MI mm; p = 0.0095). Administration of doxycycline for a limited two week period is associated with a sustained improvement in ex-vivo contractility and an increase in wall thickness at end-systole in the border zone six weeks after MI. These findings were associated with a reduction in intracellular MMP-2 activity.
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影响因子：
4
作者：
Lovett DH;Chu C;Wang G;Ratcliffe MB;Baker AJ
通讯作者：
Baker AJ
影响因子：
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MARKOVITZ, LJ;SAVAGE, EB;EDMUNDS, LH
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EDMUNDS, LH
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Schulz, R
影响因子：
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Lee, Won Woo;Marinelli, Brett;van der Laan, Anja M.;Sena, Brena F.;Gorbatov, Rostic;Leuschner, Florian;Dutta, Partha;Iwamoto, Yoshiko;Ueno, Takuya;Begieneman, Mark P. V.;Niessen, Hans W. M.;Piek, Jan J.;Vinegoni, Claudio;Pittet, Mikael J.;Swirski, Filip K.;Tawakol, Ahmed;Di Carli, Marcelo;Weissleder, Ralph;Nahrendorf, Matthias
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Nahrendorf, Matthias