The (Pro)renin Receptor/ATP6AP2 is Essential for Vacuolar H+-ATPase Assembly in Murine Cardiomyocytes
The (Pro)renin Receptor/ATP6AP2 is Essential for Vacuolar H+-ATPase Assembly in Murine Cardiomyocytes
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DOI：
10.1161/circresaha.110.224667
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发表时间：
2010-07-09
影响因子：
20.1
通讯作者：
Itoh, Hiroshi
中科院分区：
文献类型：
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作者：
Kinouchi, Kenichiro;Ichihara, Atsuhiro;Itoh, Hiroshi
原理：在ATP6AP2中编码的（pro）肾素受体[(P)RR]在局部肾素-血管紧张素系统（RAS）的激活中起关键作用。(P) RR的截断形式，称为M8.9，也被发现与液泡H+-ATPase （V-ATPase）相关，暗示ATP6AP2的非ras相关功能。目的：探讨(P)RR/ATP6AP2在小鼠心肌细胞中的作用。方法与结果：心肌细胞特异性消融Atp6ap2导致致死性心力衰竭；心肌细胞含有RAB7-和溶酶体相关膜蛋白2 （LAMP2）阳性的多泡液泡，特别是在核周围区域。肌原纤维和线粒体保留在细胞周围。心肌细胞死亡伴随着大量含有未消化细胞成分的自噬空泡，这是自噬降解受损的结果。值得注意的是，消融Atp6ap2选择性地抑制V-ATPase的V-O亚基的表达，导致细胞内囊泡脱酸。此外，巴菲霉素A1或氯喹对细胞内酸化的抑制再现了在(P)RR/ atp6ap2缺陷心肌细胞中观察到的表型。结论：基因消融Atp6ap2建立了V-ATPase功能丧失模型。ATP6AP2的基因产物被认为以两种方式起作用：(1)作为(P) RR，发挥ras相关功能；(2)作为v - atpase相关蛋白，发挥非ras相关功能，对细胞存活至关重要。（Circ Res. 2010; 107: 30-34）
Rationale: The (pro) renin receptor [(P)RR], encoded in ATP6AP2, plays a key role in the activation of local renin-angiotensin system (RAS). A truncated form of (P) RR, termed M8.9, was also found to be associated with the vacuolar H+-ATPase (V-ATPase), implicating a non-RAS-related function of ATP6AP2.Objective: We investigated the role of (P)RR/ATP6AP2 in murine cardiomyocytes.Methods and Results: Cardiomyocyte-specific ablation of Atp6ap2 resulted in lethal heart failure; the cardiomyocytes contained RAB7- and lysosomal-associated membrane protein 2 (LAMP2)-positive multivesicular vacuoles, especially in the perinuclear regions. The myofibrils and mitochondria remained at the cell periphery. Cardiomyocyte death was accompanied by numerous autophagic vacuoles that contained undigested cellular constituents, as a result of impaired autophagic degradation. Notably, ablation of Atp6ap2 selectively suppressed expression of the V-O subunits of V-ATPase, resulting in deacidification of the intracellular vesicles. Furthermore, the inhibition of intracellular acidification by treatment with bafilomycin A1 or chloroquine reproduced the phenotype observed for the (P)RR/ATP6AP2-deficient cardiomyocytes.Conclusions: Genetic ablation of Atp6ap2 created a loss-of-function model for V-ATPase. The gene product of ATP6AP2 is considered to act as in 2 ways: (1) as (P) RR, exerting a RAS-related function; and (2) as the V-ATPase-associated protein, exerting a non-RAS-related function that is essential for cell survival. (Circ Res. 2010; 107: 30-34.)