ATP6AP2 knockdown in cardiomyocyte deteriorates heart function via compromising autophagic flux and NLRP3 inflammasome activation.
ATP6AP2 knockdown in cardiomyocyte deteriorates heart function via compromising autophagic flux and NLRP3 inflammasome activation.
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心肌细胞中 ATP6AP2 敲低通过损害自噬通量和 NLRP3 炎性体激活而恶化心脏功能
DOI：
10.1038/s41420-022-00967-w
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发表时间：
2022-04-04
影响因子：
7
通讯作者：
Dong B
中科院分区：
文献类型：
--
作者：
Li L;Cui YJ;Liu Y;Li HX;Su YD;Li SN;Wang LL;Zhao YW;Wang SX;Yan F;Dong B
适度的自噬可以清除受损的蛋白质和细胞器。在一些炎症性疾病中，自噬通过抑制NOD样受体家族pyrin domain containing 3（NLRP 3）发挥保护作用。（Pro）肾素受体（PRR，或ATP 6AP 2）是自噬所需的V-ATP酶的关键组分。关于ATP 6AP 2在病理过程中的作用仍存在争议。在压力过载应激下，ATP 6AP 2对NLRP 3炎性小体和自噬通量的影响仍然未知。这项研究探讨了ATP 6AP 2，自噬通量和NLRP 3之间的潜在联系。从TAC后5天开始，野生小鼠中的ATP 6AP 2表达上调，并且这种表达保持在高水平，直到TAC后8周。同时，自噬流从早期代偿性激活转变为心力衰竭阶段的阻断。在TAC后8周可以看到NLRP 3活化。腺病毒介导的ATP 6AP 2基因敲低（shR-ATP 6AP 2）可加速心力衰竭的进展。与shR-Scr组相比，TAC诱导后shR-ATP 6AP 2组心功能和纤维化程度明显加重。同时，有NLRP 3的表达和自噬通量的阻断。构建了心脏限制性过表达ATP 6AP 2/（P）RR的转基因小鼠（Tg）。虽然在心肌组织中高表达，但在基础状态下没有自发的功能异常。心脏功能、纤维化、肥大与对照组相同。而SQSTM 1/P62降低，表明自噬通量阻断解除。此外，转染shR-ATP 6AP 2的新生大鼠心室肌细胞（NRVMs）比sh-Scr NRVMs对苯肾上腺素诱导的细胞死亡更敏感。在苯肾上腺素刺激下，shR-ATP 6AP 2组细胞内活性氧（ROS）和线粒体活性氧（mito-ROS）含量增加。在体内阻断NLRP 3活化部分地挽救了心脏功能障碍和纤维化。总之，ATP 6AP 2上调是压力超负荷的代偿反应。如果得不到有效的补偿，它会损害自噬通量，导致功能失调的线粒体积累，进一步产生ROS激活NLRP 3，最终加速心力衰竭。
Moderate autophagy can remove damaged proteins and organelles. In some inflammatory diseases, autophagy plays a protective role by inhibiting the NOD-like receptor family pyrin domain containing 3(NLRP3). (Pro)renin receptor (PRR, or ATP6AP2) is a critical component of the V-ATPase required for autophagy. It remains controversial about ATP6AP2 in the pathological process. The impact of ATP6AP2 on NLRP3 inflammasome and autophagic flux remains unknown under pressure overload stress. This research explores the potential link between ATP6AP2, autophagic flux, and NLRP3. There was upregulation of ATP6AP2 from 5-day post-TAC, and this expression remained at a high level until 8-weeks post-TAC in wild mice. Meanwhile, autophagic flux switched from early compensatory activation to blocking in the heart failure phase. NLRP3 activation can be seen at 8-week post-TAC. Adenovirus-mediated knockdown of ATP6AP2(shR-ATP6AP2) accelerated the progress of heart failure. After TAC was induced, shR-ATP6AP2 significantly deteriorated heart function and fibrosis compared with the shR-Scr group. Meanwhile, there was an elevated expression of NLRP3 and autophagic flux blockage. A transgenic mouse(Tg) with cardio-restricted ATP6AP2/(P)RR overexpression was constructed. Although high expression in cardiac tissue, there were no spontaneous functional abnormalities under the basal state. Cardiac function, fibrosis, hypertrophy remained identical to the control TAC group. However, SQSTM1/P62 was reduced, which indicated the relief of autophagic flux blockage. Further, Neonatal rat ventricular myocyte (NRVMs) transfected with shR-ATP6AP2 showed more susceptibility than sh-Scr NRVMs to phenylephrine-induced cell death. More reactive oxygen species (ROS) or mito-ROS accumulated in the shR-ATP6AP2 group when phenylephrine stimulation. Blocking NLRP3 activation in vivo partly rescued cardiac dysfunction and fibrosis. In conclusion, ATP6AP2 upregulation is a compensatory response to pressure overload. If not effectively compensated, it compromises autophagic flux, leads to dysfunctional mitochondria accumulation, further produces ROS to activate NLRP3, eventually accelerates heart failure.
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影响因子：
3.4
作者：
Dorn GW 2nd
通讯作者：
Dorn GW 2nd
影响因子：
2.5
作者：
Mizuguchi Y;Yatabe M;Morishima N;Morimoto S;Ichihara A
通讯作者：
Ichihara A
影响因子：
9.5
作者：
Liu, Yi;Lian, Kun;Tao, Ling
通讯作者：
Tao, Ling
褪黑激素通过线粒体自噬激活和 NLRP3 炎症小体抑制改善动脉粥样硬化的进展
影响因子：
--
作者：
Ma S;Chen J;Feng J;Zhang R;Fan M;Han D;Li X;Li C;Ren J;Wang Y;Cao F
通讯作者：
Cao F
影响因子：
37.8
作者：
Li DL;Wang ZV;Ding G;Tan W;Luo X;Criollo A;Xie M;Jiang N;May H;Kyrychenko V;Schneider JW;Gillette TG;Hill JA
通讯作者：
Hill JA