The valosin-containing protein is a novel repressor of cardiomyocyte hypertrophy induced by pressure overload.
The valosin-containing protein is a novel repressor of cardiomyocyte hypertrophy induced by pressure overload.
复制标题
含有缬洛辛的蛋白质是压力超负荷引起的心肌细胞肥大的新型抑制剂。
作者：
Zhou N;Ma B;Stoll S;Hays TT;Qiu H
高血压诱导的左心室肥厚（LVH）是心力衰竭的独立风险因素。LVH的消退已成为高血压患者治疗的主要目标。在这里，我们验证了我们的假设，即含有valosin的蛋白（VCP），一种ATP酶相关蛋白，是压力超负荷应激下心肌细胞肥大的一种新的阻遏物。通过超声心动图测定4个月雄性自发性高血压大鼠（SHR）与年龄匹配的血压正常Wistar京都（WKY）大鼠的左心室肥大（LVH）。VCP的表达被发现是显着下调，在左心室（LV）组织从SHR与WKY大鼠。在野生型（WT）小鼠中通过横向主动脉缩窄（TAC）诱导压力超负荷。在2周结束时，具有TAC的小鼠发展出显著的LVH，而心脏功能保持不变。与假手术对照组相比，在TAC WT小鼠中发现肥厚LV组织中VCP在mRNA和蛋白水平上均显著降低。在血管紧张素II处理后，在体外分离的新生大鼠心肌细胞中也观察到含缬沙坦蛋白VCP表达呈时间和剂量依赖性降低。相反，心脏特异性VCP过表达的转基因（TG）小鼠在2周TAC后，与同窝匹配的WT对照相比，TAC诱导的LVH显示出显著抑制。在WT小鼠LV中观察到的TAC诱导的雷帕霉素复合物1（mTORC 1）信号传导机制靶点的激活在VCP TG小鼠中也显著减弱。总之，VCP作为一种新的阻遏物，能够通过调节mTORC1信号通路来防止心肌细胞肥大。
Hypertension‐induced left ventricular hypertrophy (LVH) is an independent risk factor for heart failure. Regression of LVH has emerged as a major goal in the treatment of hypertensive patients. Here, we tested our hypothesis that the valosin‐containing protein (VCP), an ATPase associate protein, is a novel repressor of cardiomyocyte hypertrophy under the pressure overload stress. Left ventricular hypertrophy (LVH) was determined by echocardiography in 4‐month male spontaneously hypertensive rats (SHRs) vs. age‐matched normotensive Wistar Kyoto (WKY) rats. VCP expression was found to be significantly downregulated in the left ventricle (LV) tissues from SHRs vs. WKY rats. Pressure overload was induced by transverse aortic constriction (TAC) in wild‐type (WT) mice. At the end of 2 weeks, mice with TAC developed significant LVH whereas the cardiac function remained unchanged. A significant reduction of VCP at both the mRNA and protein levels in hypertrophic LV tissue was found in TAC WT mice compared to sham controls. Valosin‐containing protein VCP expression was also observed to be time‐ and dose‐dependently reduced in vitro in isolated neonatal rat cardiomyocytes upon the treatment of angiotensin II. Conversely, transgenic (TG) mice with cardiac‐specific overexpression of VCP showed a significant repression in TAC‐induced LVH vs. litter‐matched WT controls upon 2‐week TAC. TAC‐induced activation of the mechanistic target of rapamycin complex 1 (mTORC1) signaling observed in WT mice LVs was also significantly blunted in VCP TG mice. In conclusion, VCP acts as a novel repressor that is able to prevent cardiomyocyte hypertrophy from pressure overload by modulating the mTORC1 signaling pathway.
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影响因子：
5.6
作者：
Kemi, Ole Johan;Ceci, Marcello;Ellingsen, Oyvind
通讯作者：
Ellingsen, Oyvind
影响因子：
0.2
作者：
Misra, Kumar Haraprasad;Das, Mangala Charana;Ramani, Y. Roja
通讯作者：
Ramani, Y. Roja
影响因子：
0.9
作者：
Paoletti, E.;Cannella, G.
通讯作者：
Cannella, G.
影响因子：
4
作者：
Bulfer SL;Chou TF;Arkin MR
通讯作者：
Arkin MR
DOI：
10.1161/hypertensionaha.117.09026
发表时间：
2017-08
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Niiranen TJ;Lyass A;Larson MG;Hamburg NM;Benjamin EJ;Mitchell GF;Vasan RS
通讯作者：
Vasan RS