AMPKα1 deletion in myofibroblasts exacerbates post-myocardial infarction fibrosis by a connexin 43 mechanism.
AMPKα1 deletion in myofibroblasts exacerbates post-myocardial infarction fibrosis by a connexin 43 mechanism.
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DOI：
10.1007/s00395-021-00846-y
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发表时间：
2021-02-09
影响因子：
9.5
通讯作者：
Horman S
中科院分区：
文献类型：
--
作者：
Dufeys C;Daskalopoulos EP;Castanares-Zapatero D;Conway SJ;Ginion A;Bouzin C;Ambroise J;Bearzatto B;Gala JL;Heymans S;Papageorgiou AP;Vinckier S;Cumps J;Balligand JL;Vanhaverbeke M;Sinnaeve P;Janssens S;Bertrand L;Beauloye C;Horman S
我们先前已经证明，全身AMP激活的蛋白激酶α1(AMPKα1)的失效通过促进成纤维细胞的增殖来促进不良的左室重构，而肌肉分化和瘢痕成熟则受到损害。因此，我们假设成纤维细胞AMPKα1是调节梗死心肌纤维化的关键信号元件，是治疗干预的一个有吸引力的靶点。本研究旨在探讨肌成纤维细胞特异性缺失AMPKα1基因对心肌梗死(MI)后左心适应的影响及其分子机制。Mf限制性AMPKα1条件性基因敲除小鼠永久结扎冠状动脉左前降支。与野生型(WT)心脏相比，CKO心脏表现出心肌梗死后加重的不利的左室重构，并以夸大的纤维化反应为特征。CKO梗死区心肌成纤维细胞增殖和MF含量显著增加，MFS连接蛋白43(Cx43)表达显著降低。从机制上讲，AMPKmiR-125b-5p通过转录和转录后机制影响α-43的表达。总而言之，我们的数据表明，MF-AMPKα1作为心脏纤维化和重塑的主要调节因子，可能成为药物抗纤维化应用的新的潜在靶点。网上版载有补充材料，可在10.1007/s00395-021-00846-y查阅。
We have previously demonstrated that systemic AMP-activated protein kinase α1 (AMPKα1) invalidation enhanced adverse LV remodelling by increasing fibroblast proliferation, while myodifferentiation and scar maturation were impaired. We thus hypothesised that fibroblastic AMPKα1 was a key signalling element in regulating fibrosis in the infarcted myocardium and an attractive target for therapeutic intervention. The present study investigates the effects of myofibroblast (MF)-specific deletion of AMPKα1 on left ventricular (LV) adaptation following myocardial infarction (MI), and the underlying molecular mechanisms. MF-restricted AMPKα1 conditional knockout (cKO) mice were subjected to permanent ligation of the left anterior descending coronary artery. cKO hearts exhibit exacerbated post-MI adverse LV remodelling and are characterised by exaggerated fibrotic response, compared to wild-type (WT) hearts. Cardiac fibroblast proliferation and MF content significantly increase in cKO infarcted hearts, coincident with a significant reduction of connexin 43 (Cx43) expression in MFs. Mechanistically, AMPKα1 influences Cx43 expression by both a transcriptional and a post-transcriptional mechanism involving miR-125b-5p. Collectively, our data demonstrate that MF-AMPKα1 functions as a master regulator of cardiac fibrosis and remodelling and might constitute a novel potential target for pharmacological anti-fibrotic applications. The online version contains supplementary material available at 10.1007/s00395-021-00846-y.
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AMPK激活通过减少O-Glcnacylation来抵消心脏肥大。
影响因子：
16.6
作者：
Gélinas R;Mailleux F;Dontaine J;Bultot L;Demeulder B;Ginion A;Daskalopoulos EP;Esfahani H;Dubois-Deruy E;Lauzier B;Gauthier C;Olson AK;Bouchard B;Des Rosiers C;Viollet B;Sakamoto K;Balligand JL;Vanoverschelde JL;Beauloye C;Horman S;Bertrand L
通讯作者：
Bertrand L
影响因子：
37.8
作者：
Cerqueira, MD;Weissman, NJ;Verani, MS
通讯作者：
Verani, MS
影响因子：
4
作者：
Jin, Zheng;Xu, Songbai;Zhao, Gang
通讯作者：
Zhao, Gang
影响因子：
5.8
作者：
Ionta M;Ferreira RA;Pfister SC;Machado-Santelli GM
通讯作者：
Machado-Santelli GM
影响因子：
3.4
作者：
Fontes, Magda S. C.;van Veen, Loon A. B.;van Rijen, Harold V. M.
通讯作者：
van Rijen, Harold V. M.