Deubiquitinase Ubiquitin-Specific Protease 10 Deficiency Regulates Sirt6 signaling and Exacerbates Cardiac Hypertrophy.
Deubiquitinase Ubiquitin-Specific Protease 10 Deficiency Regulates Sirt6 signaling and Exacerbates Cardiac Hypertrophy.
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去泛素酶泛素特异性蛋白酶 10 缺乏调节 Sirt6 信号传导并加剧心脏肥大
DOI：
10.1161/jaha.120.017751
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发表时间：
2020-11-17
影响因子：
5.4
通讯作者：
Zhang YZ
中科院分区：
文献类型：
--
作者：
Zhang DH;Zhang JL;Huang Z;Wu LM;Wang ZM;Li YP;Tian XY;Kong LY;Yao R;Zhang YZ
心脏肥大（CH）是一种对血压超负荷进行代偿的生理反应。在病理条件下，由于心肌细胞和心脏组织的无序生长，肥大可能会发展为心力衰竭。泛素特异性蛋白酶10（USP10）是半胱氨酸蛋白酶泛素特异性蛋白酶家族的成员，该家族参与病毒感染、氧化应激、脂滴形成和热休克等过程。然而，USP10在心脏肥大中的作用在很大程度上仍不明确。在此，我们对USP10在心脏肥大中的作用展开了研究。
我们利用心脏特异性USP10基因敲除（USP10 - CKO）小鼠和USP10转基因（USP10 - TG）小鼠，来研究主动脉缩窄后USP10在心脏肥大中的作用。我们还在分离的心肌细胞中进一步研究了USP10的具体功能。在主动脉缩窄后的小鼠肥厚心脏以及对肥大激动剂产生反应的分离心肌细胞中，USP10的表达均有所增加。心脏中USP10缺失的小鼠在压力超负荷应激后，表现出更为严重的心脏肥大和纤维化，进而导致心脏收缩功能恶化。相反，心脏中USP10的过表达可抵御压力超负荷诱导的适应性不良的心脏肥大。从机制上来说，我们证明了在血管紧张素II作用下，USP10的激活及其与Sirt6的相互作用，会导致Sirt6的泛素化显著增加，进而致使Akt信号通路下调，心肌细胞肥大得到缓解。相应地，USP10的失活会降低Sirt6的丰度和稳定性，并减弱Sirt6在心肌细胞中诱导的下游信号传导。
USP10作为一种Sirt6去泛素化酶，会诱导心肌细胞肥大并引发适应性不良的心脏肥大。
Cardiac hypertrophy (CH) is a physiological response that compensates for blood pressure overload. Under pathological conditions, hypertrophy can progress to heart failure as a consequence of the disorganized growth of cardiomyocytes and cardiac tissue. USP10 (ubiquitin‐specific protease 10) is a member of the ubiquitin‐specific protease family of cysteine proteases, which are involved in viral infection, oxidative stress, lipid drop formation, and heat shock. However, the role of USP10 in CH remains largely unclear. Here, we investigated the roles of USP10 in CH. Cardiac‐specific USP10 knockout (USP10‐CKO) mice and USP10‐transgenic (USP10‐TG) mice were used to examined the role of USP10 in CH following aortic banding. The specific functions of USP10 were further examined in isolated cardiomyocytes. USP10 expression was increased in murine hypertrophic hearts following aortic banding and in isolated cardiomyocytes in response to hypertrophic agonist. Mice deficient in USP10 in the heart exhibited exaggerated cardiac hypertrophy and fibrosis following pressure overload stress, which resulted in worsening of cardiac contractile function. In contrast, cardiac overexpression of USP10 protected against pressure overload‐induced maladaptive CH. Mechanistically, we demonstrated that USP10 activation and interaction with Sirt6 in response to angiotensin II led to a marked increase in the ubiquitination of Sirt6 and resulted in Akt signaling downregulation and attenuation of cardiomyocyte hypertrophy. Accordingly, inactivation of USP10 reduced Sirt6 abundance and stability and diminished Sirt6‐induced downstream signaling in cardiomyocytes. USP10 functions as a Sirt6 deubiquitinase that induces cardiac myocyte hypertrophy and triggers maladaptive CH.