The Downregulation of ADAM17 Exerts Protective Effects against Cardiac Fibrosis by Regulating Endoplasmic Reticulum Stress and Mitophagy.
The Downregulation of ADAM17 Exerts Protective Effects against Cardiac Fibrosis by Regulating Endoplasmic Reticulum Stress and Mitophagy.
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ADAM17 的下调通过调节内质网应激和线粒体自噬对心脏纤维化发挥保护作用
DOI：
10.1155/2021/5572088
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发表时间：
2021
影响因子：
--
通讯作者：
Wang JF
中科院分区：
文献类型：
--
作者：
Guan C;Zhang HF;Wang YJ;Chen ZT;Deng BQ;Qiu Q;Chen SX;Wu MX;Chen YX;Wang JF
A崩解素和金属蛋白酶17 （ADAM17）是一种广泛表达于多种组织的跨膜蛋白；它介导许多膜结合分子的脱落，涉及细胞-细胞和细胞-基质相互作用。我们研究了小鼠心脏成纤维细胞（mcf）中ADAM17在心脏纤维化中的作用。从新生小鼠心脏中分离出mcf。观察ADAM17对TGF-β1诱导mcf向肌成纤维细胞分化及纤维化行为的影响。采用qRT-PCR和western blotting检测I型胶原、α-SMA等纤维化蛋白的表达水平。采用CCK-8和伤口愈合实验检测细胞增殖和迁移。为了确定ADAM17的靶基因，在ADAM17沉默后，我们评估了内质网（ER）应激组分和PINK1/Parkin通路的蛋白水平。我们还研究了ADAM17沉默或用thapsigargin（急性内质网应激的关键刺激因子）治疗对mcf增殖、迁移和胶原分泌的影响。在体内，我们采用左前降支结扎法建立小鼠心肌纤维化模型；术后给予选择性ADAM17抑制剂（TMI-005）灌胃4周。我们发现，在纤维化心脏组织和TGF-β1处理的mcf中，ADAM17的表达水平更高。adam17特异性sirna降低TGF-β1诱导的mcf胶原分泌、增殖和迁移的增加。ADAM17的敲低通过抑制内质网应激的ATF6分支，进一步激活线粒体自噬，从而降低mcf的激活。此外，ADAM17表达降低还能改善心脏纤维化和改善心脏功能。本研究强调mCF ADAM17表达通过调节内质网应激和线粒体自噬在心脏纤维化中发挥关键作用，从而限制纤维化，改善心功能。因此，ADAM17下调在生理范围内对心脏纤维化具有保护作用。
A disintegrin and metalloproteinase 17 (ADAM17) is a transmembrane protein that is widely expressed in various tissues; it mediates the shedding of many membrane-bound molecules, involving cell-cell and cell-matrix interactions. We investigated the role of ADAM17 within mouse cardiac fibroblasts (mCFs) in heart fibrosis. mCFs were isolated from the hearts of neonatal mice. Effects of ADAM17 on the differentiation of mCFs towards myofibroblasts and their fibrotic behaviors following induction with TGF-β1 were examined. The expression levels of fibrotic proteins, such as collagen I and α-SMA, were assessed by qRT-PCR analysis and western blotting. Cell proliferation and migration were measured using the CCK-8 and wound healing assay. To identify the target gene for ADAM17, the protein levels of the components of endoplasmic reticulum (ER) stress and the PINK1/Parkin pathway were assessed following ADAM17 silencing. The effects of ADAM17 silencing or treatment with thapsigargin, a key stimulator of acute ER stress, on mCFs proliferation, migration, and collagen secretion were also examined. In vivo, we used a mouse model of cardiac fibrosis established by left anterior descending artery ligation; the mice were administered oral gavage with a selective ADAM17 inhibitor (TMI-005) for 4 weeks after the operation. We found that the ADAM17 expression levels were higher in fibrosis heart tissues and TGF-β1-treated mCFs. The ADAM17-specific siRNAs decreased TGF-β1-induced increase in the collagen secretion, proliferation, and migration of mCFs. Knockdown of ADAM17 reduces the activation of mCFs by inhibiting the ATF6 branch of ER stress and further activating mitophagy. Moreover, decreased ADAM17 expression also ameliorated cardiac fibrosis and improved heart function. This study highlights that mCF ADAM17 expression plays a key role in cardiac fibrosis by regulating ER stress and mitophagy, thereby limiting fibrosis and improving heart function. Therefore, ADAM17 downregulation, within the physiological range, could exert protective effects against cardiac fibrosis.
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影响因子：
3.4
作者：
Qiao H;Ren H;Du H;Zhang M;Xiong X;Lv R
通讯作者：
Lv R
DOI：
10.1161/hypertensionaha.112.192500
发表时间：
2012-07
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Galán M;Kassan M;Choi SK;Partyka M;Trebak M;Henrion D;Matrougui K
通讯作者：
Matrougui K
影响因子：
4.6
作者：
Moss ML;Minond D
通讯作者：
Minond D
影响因子：
15.9
作者：
Khalil, Hadi;Kanisicak, Onur;Molkentin, Jeffery D.
通讯作者：
Molkentin, Jeffery D.
DOI：
10.1161/atvbaha.117.309430
发表时间：
2017-06
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Dou H;Feher A;Davila AC;Romero MJ;Patel VS;Kamath VM;Gooz MB;Rudic RD;Lucas R;Fulton DJ;Weintraub NL;Bagi Z
通讯作者：
Bagi Z