Activation of Gαq in Cardiomyocytes Increases Vps34 Activity and Stimulates Autophagy.
Activation of Gαq in Cardiomyocytes Increases Vps34 Activity and Stimulates Autophagy.
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DOI：
10.1097/fjc.0000000000000461
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发表时间：
2017-04
影响因子：
3
通讯作者：
Lin RZ
中科院分区：
文献类型：
--
作者：
Liu S;Jiang YP;Ballou LM;Zong WX;Lin RZ
激活异源三聚体G蛋白Gαq的受体被认为在心力衰竭的发展中起作用。自噬的失调发生在一些病理性心脏疾病中，包括心力衰竭，但Gαq是否参与这一过程尚不清楚。我们使用心肌细胞特异性的诱导型Gαq激活转基因小鼠模型（称为Gα qQ 209 L）来解决这个问题。Gαq激活7天后，Gα qQ 209 L心脏比野生型（WT）心脏含有更多的自噬空泡。还观察到参与自噬的蛋白质水平增加，特别是p62和LC 3-II。LysoTracker染色和Western blotting显示，Gα qQ 209 L心肌中溶酶体的数量和大小以及溶酶体蛋白水平增加，表明溶酶体降解活性增强。重要的是，在分离的成年心肌细胞中测量LC 3-II更新的自噬通量测定表明，自噬活性在Gα qQ 209 L心脏中增强。Gα qQ 209 L心脏表现出自噬起始复合物水平升高，该复合物含有III类磷酸肌醇3-激酶Vps 34。因此，Gα qQ 209 L心脏中的Vps 34活性和磷脂酰肌醇3-磷酸水平高于WT心脏，从而解释了自噬空泡丰度较高的原因。这些结果表明，自噬的增加是心脏对Gαq激活的早期反应。
Receptors that activate the heterotrimeric G protein Gαq are thought to play a role in the development of heart failure. Dysregulation of autophagy occurs in some pathological cardiac conditions including heart failure, but whether Gαq is involved in this process is unknown. We used a cardiomyocyte-specific transgenic mouse model of inducible Gαq activation (termed GαqQ209L) to address this question. After 7 days of Gαq activation, GαqQ209L hearts contained more autophagic vacuoles than wild type (WT) hearts. Increased levels of proteins involved in autophagy, especially p62 and LC3-II, were also seen. LysoTracker staining and western blotting showed that the number and size of lysosomes and lysosomal protein levels were increased in GαqQ209L hearts, indicating enhanced lysosomal degradation activity. Importantly, an autophagic flux assay measuring LC3-II turnover in isolated adult cardiomyocytes indicated that autophagic activity is enhanced in GαqQ209L hearts. GαqQ209L hearts exhibited elevated levels of the autophagy initiation complex, which contains the Class III phosphoinositide 3-kinase Vps34. As a consequence, Vps34 activity and phosphatidylinositol 3-phosphate levels were higher in GαqQ209L hearts than WT hearts, thus accounting for the higher abundance of autophagic vacuoles. These results indicate that an increase in autophagy is an early response to Gαq activation in the heart.