Department of Cardiology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, PR China.
Cardiovascular Research Institute of Wuhan University, Jiefang Road 238, Wuhan, PR China.
Cardiovasc Res. 2019 May 1;115(6):1067-1077. doi: 10.1093/cvr/cvy279.
C1q-tumour necrosis factor-related protein-3 (CTRP3) is an adipokine and a paralog of adiponectin. Our previous study showed that CTRP3 attenuated diabetes-related cardiomyopathy. However, the precise role of CTRP3 in cardiac hypertrophy remains unclear. This study was aimed to clarify the role of CTRP3 involved in cardiac hypertrophy.
Cardiomyocyte-specific CTRP3 overexpression was achieved using an adeno-associated virus system, and cardiac CTRP3 expression was knocked down using gene delivery of specific short hairpin RNAs in vivo. CTRP3 expression was upregulated in murine hypertrophic hearts and failing human hearts. Increased CTRP3 was mainly derived from cardiomyocytes and induced by the production of reactive oxygen species (ROS) during the hypertrophic response. CTRP3-overexpressing mice exhibited exacerbated cardiac hypertrophy and cardiac dysfunction in response to pressure overload. Conversely, Ctrp3 deficiency in the heart resulted in an alleviated hypertrophic phenotype. CTRP3 induced hypertrophy in cardiomyocytes, which could be blocked by the addition of CTRP3 antibody in the media. Detection of signalling pathways showed that pressure overload-induced activation of the transforming growth factor β-activated kinase 1 (TAK1)-c-Jun N-terminal kinase (JNK) pathway was enhanced by CTRP3 overexpression and inhibited by CTRP3 disruption. Furthermore, we found that CTRP3 lost its pro-hypertrophic effects in cardiomyocyte-specific Tak1 knockout mice. Protein kinase A (PKA) was involved in the activation of TAK1 by CTRP3.
In conclusion, our results suggest that CTRP3 promotes pressure overload-induced cardiac hypertrophy via activation of the TAK1-JNK axis.
C1q 肿瘤坏死因子相关蛋白 3（CTRP3）是一种脂肪因子，也是脂联素的同源物。我们之前的研究表明，CTRP3 可减轻与糖尿病相关的心肌病。然而，CTRP3 在心肌肥厚中的确切作用尚不清楚。本研究旨在阐明 CTRP3 在心肌肥厚中的作用。
通过腺相关病毒系统实现心肌细胞特异性 CTRP3 过表达，并在体内通过特定短发夹 RNA 的基因传递敲低心脏中的 CTRP3 表达。CTRP3 在小鼠肥厚心脏和衰竭的人类心脏中表达上调。CTRP3 增加主要来自心肌细胞，并在肥厚反应期间由活性氧（ROS）的产生诱导。CTRP3 过表达小鼠在应对压力超负荷时表现出更严重的心脏肥厚和心功能障碍。相反，心脏中 Ctrp3 的缺失导致肥厚表型减轻。CTRP3 在心肌细胞中诱导肥大，可通过在培养基中添加 CTRP3 抗体加以阻断。检测信号通路表明，CTRP3 过表达增强了压力超负荷诱导的转化生长因子β激活激酶 1（TAK1）-c-Jun N 末端激酶（JNK）通路的激活，而 CTRP3 破坏则抑制了该通路的激活。此外，我们发现 CTRP3 在心肌细胞特异性 Tak1 敲除小鼠中失去了其促肥厚作用。蛋白激酶 A（PKA）参与了 CTRP3 对 TAK1 的激活。
总之，我们的研究结果表明，CTRP3 通过激活 TAK1-JNK 轴促进压力超负荷诱导的心脏肥厚。
