C1q-TNF-related protein-3 attenuates pressure overload-induced cardiac hypertrophy by suppressing the p38/CREB pathway and p38-induced ER stress
C1q-TNF-related protein-3 attenuates pressure overload-induced cardiac hypertrophy by suppressing the p38/CREB pathway and p38-induced ER stress
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C1q-TNF 相关蛋白 3 通过抑制 p38/CREB 通路和 p38 诱导的 ER 应激来减轻压力超负荷诱导的心脏肥大
DOI：
10.1038/s41419-019-1749-0
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发表时间：
2019-07-08
影响因子：
9
通讯作者：
Yi, Wei
中科院分区：
文献类型：
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作者：
Zhang, Bing;Zhang, Ping;Yi, Wei
c1q -肿瘤坏死因子相关蛋白-3 （CTRP3）是一种脂肪因子，在缺血性或糖尿病性心脏损伤中发挥保护作用。然而，CTRP3在心肌肥厚中的作用尚不清楚。本研究旨在探讨CTRP3对高血压引起的病理性心肌肥厚的药理作用。雄性C57BL/6 J野生型（WT）小鼠、ctrp3基因敲除小鼠和慢病毒过表达小鼠ctrp3感染小鼠分别进行假手术或横断主动脉缩窄（TAC）手术。4周后观察心肌肥厚、纤维化、心功能变化。与WT小鼠相比，ctrp3缺失严重损害了心肌细胞的收缩功能障碍，加剧了心肌细胞的扩大和心肌纤维化，并重新编程了TAC后病理基因的表达。反之，CTRP3过表达在TAC后小鼠左心室心脏收缩功能恢复、心肌肥厚纤维化减轻、肥厚纤维化信号表达抑制等方面发挥作用。此外，CTRP3还调控p38/CREB通路和内质网应激的主要调节因子GRP78及其下游分子真核翻译抑制因子2 α、C/EBP同源蛋白和肌醇需要酶1的表达。此外，SB203580对p38 MAPK的抑制减弱了由于ctrp3缺乏而加剧的内质网应激。在体外，CTRP3保护新生大鼠心肌细胞免受苯肾上腺素诱导的心肌细胞肥大。我们得出结论，CTRP3主要通过抑制p38/CREB通路和减轻p38诱导的内质网应激来保护宿主免受压力过载引起的病理性心脏重构和左心室功能障碍。
C1q-tumor necrosis factor-related protein-3 (CTRP3) is an adipokine, which exerts protective function in ischemic or diabetic heart injury. However, the role of CTRP3 in cardiac hypertrophy remains unclear. The aim of this study was to investigate the pharmacological effects of CTRP3 on pathological cardiac hypertrophy induced by hypertension. Male C57BL/6 J wild-type (WT) mice,Ctrp3knockout mice, and mice infected with lentivirus overexpressing mouseCtrp3underwent sham surgery or transverse aortic constriction (TAC) surgery. After 4 weeks, cardiac hypertrophy, fibrosis, and cardiac function were examined. Compared with WT mice,Ctrp3deficiency substantially impaired contractile dysfunction, exacerbated the enlargement of cardiomyocytes and myocardial fibrosis, and reprogramed the expression of pathological genes after TAC. Conversely, CTRP3 overexpression played a role in restoring the left ventricular cardiac contractile function, alleviating cardiac hypertrophy and fibrosis, and inhibiting the expression of hypertrophic and fibrotic signaling in mice after TAC. Furthermore, CTRP3 regulated the expression of the p38/CREB pathway and of the primary modulating factors of the endoplasmic reticulum stress, i.e., GRP78 and the downstream molecules eukaryotic translation inhibition factor 2 submit α, C/EBP homologous protein, and inositol-requiring enzyme-1. Further, inhibition of p38 MAPK by SB203580 blunted the ER stress intensified byCtrp3deficiency. In vitro, CTRP3 protected neonatal rat cardiac myocytes against phenylephrine-induced cardiomyocyte hypertrophy. We conclude that CTRP3 protects the host against pathological cardiac remodeling and left ventricular dysfunction induced by pressure overload largely by inhibiting the p38/CREB pathway and alleviating p38-induced ER stress.