Different roles of BAG3 in cardiac physiological hypertrophy and pathological remodeling
Different roles of BAG3 in cardiac physiological hypertrophy and pathological remodeling
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BAG3在心脏生理性肥厚和病理性重构中的不同作用
DOI：
10.1016/j.trsl.2021.02.004
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发表时间：
2021-06-03
影响因子：
7.8
通讯作者：
Sun, Yingxian
中科院分区：
文献类型：
--
作者：
Jia, Pengyu;Wu, Nan;Sun, Yingxian
心力衰竭是世界范围内导致死亡的主要原因之一。受刺激的心脏会发生适应性生理性肥厚，维持正常的心脏功能，或者发生不适应的病理性重塑，使心脏功能恶化。这两种重构常同时发生在许多心脏病的早期，对心功能有重要影响。bcl2相关的无氧基因3 （BAG3）蛋白在心脏中高度表达，具有多种功能。然而，BAG3在生理性肥大和病理性重塑过程中的调控机制和功能尚不清楚。我们建立了他莫昔芬诱导的心脏特异性杂合和纯合BAG3敲除小鼠模型（他莫昔芬给药后，心脏中BAG3蛋白水平分别下降了约40%和80%）。对BAG3敲除模型进行游泳训练或输注苯肾上腺素（PE）诱导心脏生理性肥厚和病理性重构。利用新生大鼠心室心肌细胞（NRVCs）体外研究BAG3的功能和作用机制。我们发现BAG3在体内和体外的生理性肥大和病理性重塑中均上调。杂合子或纯合子敲除小鼠心脏中的BAG3和nrvc中BAG3的敲除会减弱生理性肥大和加重病理性重构，而BAG3的过表达则会促进nrvc的生理性肥大和抑制病理性重构。从机制上讲，BAG3在nrvc中的过表达通过激活蛋白激酶B (AKT)/雷帕霉素（mTOR）通路的哺乳动物（或机制）靶点来促进生理性肥大。NRVCs中BAG3敲低通过激活活化T细胞的钙调神经磷酸酶/核因子2 （NFATc2）途径加重病理性重构。由于BAG3在心脏重塑中具有双重作用，因此心脏特异性调节BAG3可能是一种有效的治疗策略，可以防止许多心脏病引起的心功能恶化和心力衰竭。（翻译研究2021；233:47-61）
Heart failure is one of the leading causes of death worldwide. A stimulated heart undergoes either adaptive physiological hypertrophy, which can maintain a normal heart function, or maladaptive pathological remodeling, which can deteriorate heart function. These 2 kinds of remodeling often co-occur at the early stages of many heart diseases and have important effects on cardiac function. The Bcl2associated athanogene 3 (BAG3) protein is highly expressed in the heart and has many functions. However, it is unknown how BAG3 is regulated and what its function is during physiological hypertrophy and pathological remodeling. We generated tamoxifen-induced, heart-specific heterozygous and homozygous BAG3 knockout mouse models (BAG3 protein level decreased by approximately 40% and 80% in the hearts after tamoxifen administration). BAG3 knockout models were subjected to swimming training or phenylephrine (PE) infusion to induce cardiac physiological hypertrophy and pathological remodeling. Neonatal rat ventricular cardiomyocytes (NRVCs) were used to study BAG3 functions and mechanisms in vitro. We found that BAG3 was upregulated in physiological hypertrophy and in pathological remodeling both in vivo and in vitro. Heterozygous or homozygous knockout BAG3 in mouse hearts and knockdown of BAG3 in the NRVCs blunted physiological hypertrophy and aggravated pathological remodeling, while overexpression of BAG3 promoted physiological hypertrophy and inhibited pathological remodeling in NRVCs. Mechanistically, BAG3 overexpression in NRVCs promoted physiological hypertrophy by activating the protein kinase B (AKT)/mammalian (or mechanistic) target of rapamycin (mTOR) pathway. BAG3 knockdown in NRVCs aggravated pathological remodeling through activation of the calcineurin/nuclear factor of activated T cells 2 (NFATc2) pathway. Because BAG3 has a dual role in cardiac remodeling, heart-specific regulation of BAG3 may be an effective therapeutic strategy to protect against deterioration of heart function and heart failure caused by many heart diseases. (Translational Research 2021; 233:47-61)