Apelin protects against myocardial ischemic injury by inhibiting dynamin-related protein 1.
Apelin protects against myocardial ischemic injury by inhibiting dynamin-related protein 1.
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Apelin 通过抑制动力相关蛋白 1 预防心肌缺血性损伤
DOI：
10.18632/oncotarget.21777
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发表时间：
2017-11-21
期刊：
影响因子：
--
通讯作者：
Shan H
中科院分区：
文献类型：
--
作者：
Xu W;Yu H;Ma R;Ma L;Liu Q;Shan H;Wu C;Zhang R;Zhou Y;Shan H
已知动力蛋白相关蛋白1(Drp1)介导的线粒体分裂在心肌梗死(MI)的缺血性损伤中起重要作用。Apelin是Apelin受体的内源性配体，是心血管疾病的关键调节因子。在这里，我们研究了Apelin对心肌梗死损伤的影响和潜在的机制。成年雄性C57BL/6J小鼠用Apelin处理4周后，结扎冠状动脉(LAD)诱导心肌梗死，观察Apelin对LAD后6h心肌损伤的保护作用。心肌梗死组线粒体分裂明显增加，表现为磷酸化的Drp1(p-Drp1ser616)表达增强，但不影响总DRP-1水平，线粒体退化为短杆状，这是典型的分裂。Apelin可显著抑制心肌梗死后p-Drp1ser616的表达，保护线粒体形态。在低氧条件下，Apelin对原代培养的心肌细胞也有类似的作用。Apelin可减少缺氧诱导的心肌细胞凋亡，表现为TUNEL阳性细胞减少，线粒体膜电位(Mp)保持不变。Apelin可降低Bax/Bcl2比值，抑制细胞色素C的释放，抑制caspase-9和caspase-3的活化。最后，Apelin缩小了心肌梗死小鼠的梗塞范围，并使受损的心功能正常化，这一点通过挽救MI小鼠减少的射血功能和缩短分数来表明。综上所述，Apelin通过抑制p-Drp1Ser616来阻止线粒体分裂，从而防止了基质金属蛋白酶的丢失，并抑制了线粒体介导的细胞凋亡。这些结果表明，Apelin抑制DRP-1的激活是其抗心肌梗死损伤的新机制。
It is known that dynamin-related protein 1 (Drp1)-mediated mitochondrial fission plays an important role in ischemic injury of myocardial infarction (MI). Apelin, an endogenous ligand for Apelin receptor, acts as a key modulator of cardiovascular diseases. Here, we examined the effects of Apelin on MI injury and underlying mechanisms. Adult male C57BL/6J mice were treated with Apelin for 4 weeks and then subjected coronary artery ligation (LAD) to induce MI and the protective effects of Apelin on MI injury were evaluated at 6 h post LAD. Mitochondrial fission was significantly increased in MI as evidenced by enhanced expression of phosphorylated Drp1 (p-Drp1ser 616) without affecting total Drp-1 level and degenerative transformation of mitochondria into short rods as typical fission. Apelin markedly inhibited p-Drp1ser 616 and preserved mitochondrial morphology in MI. Similar effects of Apelin were consistently observed in primary cultured cardiomyocytes under hypoxia. Apelin decreased hypoxia-induced cardiomyocyte apoptosis as evidenced by decreased TUNEL-positive cells and preserved mitochondrial membrane potential (MMP). Apelin decreased Bax/Bcl-2 ratio and limited the release of cytochrome C and activation of caspase-9 and caspase-3 both in vivo and in vitro. Finally, Apelin diminished the infarct size and normalized the impaired cardiac function as indicated by rescuing of the decreased ejection faction and fractional shortening in MI mice. In conclusion, Apelin prevented mitochondrial fission by inhibiting p-Drp1Ser616, which prevents loss of MMP and inhibits the mitochondria-mediated apoptosis. These results indicate that the inhibition of Drp-1 activation by Apelin is a novel mechanism of cardioprotection against MI injury.
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影响因子：
--
作者：
Li Y;Zhang X;Yang J;Zhang Y;Zhu D;Zhang L;Zhu Y;Li D;Zhou J
通讯作者：
Zhou J
抑制动力相关蛋白 1 可预防糖尿病小鼠心肌缺血再灌注损伤
影响因子：
9.3
作者：
Ding M;Dong Q;Liu Z;Liu Z;Qu Y;Li X;Huo C;Jia X;Fu F;Wang X
通讯作者：
Wang X
影响因子：
5.2
作者：
Chang CR;Blackstone C
通讯作者：
Blackstone C
DOI：
10.1016/s0167-4889(00)00143-9
发表时间：
2001-04-23
影响因子：
5.1
作者：
Kawamata, Y;Fukusumi, S;Fujino, M
通讯作者：
Fujino, M
DOI：
10.1152/ajpheart.00413.2008
发表时间：
2008-08-01
影响因子：
4.8
作者：
Yamazaki, Katrina Go;Romero-Perez, Diego;Villarreal, Francisco
通讯作者：
Villarreal, Francisco