血管紧张素II（Ang II）受体AT1激活促进心肌肥大，而受体AT2激活可抑制AT1导致的心肌肥大，但也可通过PLZF促进心肌肥大。AT2还可与金属蛋白酶组织抑制剂3（TIMP3）结合，但其对心肌肥大的影响尚待研究。我们发现敲除TIMP3可减轻Ang II诱导的心肌肥大，但机制不明。我们的预实验显示：低浓度TIMP3抑制心肌细胞肥大，而较高浓度TIMP3则促进心肌肥大。因此我们假设：低浓度TIMP3通过抑制ADAMs/EGFR/STAT3减轻心肌肥大，而高浓度TIMP3则通过激活AT2/PLZF/GATA4促进心肌肥大。本项目拟在细胞和动物水平上，过表达和沉默相关基因，检测ADAMs活性、受体的结合与活化、信号分子的表达与活性变化等指标，探索TIMP3对心肌肥大的浓度依赖性的双向调节作用和机制，以期为阐明TIMP3在心肌肥大中的作用提供新见解。

The activation of Angiotensin II (Ang II) type 1 receptor (AT1) by Ang II promotes cardiac hypertrophy, which can be suppressed by activation of type 2 receptor (AT2). However, activation of AT2 is also able to trigger cardiac hypertrophy via PLZF (promyelocytic leukemia zinc finger). It has been proved that AT2 can bind tissue inhibitor of metalloproteinase-3 (TIMP3), but its role in cardiac hypertrophy demands investigation. Our previous work has shown that Ang II-induced cardiac hypertrophy is blocked in TIMP3-deficient mice, but its mechanism is unknown. Our preliminary data showed that low concentration of TIMP3 could inhibit cardiomyocyte hypertrophy, whereas higher concentration of TIMP3 promoted cardiomyocyte hypertrophy. Therefore, we hypothesize that low concentration of TIMP3 may inhibit cardiac hypertrophy by suppression of ADAMs (A disintegrin and metalloproteinases)/EGFR (epidermal growth factor receptor)/STAT3 (signal transducer and activator of transcription 3) and ERK1/2, while higher concentration of TIMP3 may trigger cardiac hypertrophy via activation of AT2/PLZF/ p85alpha PI3K and GATA4. This project will be done on both cellular and animal levels. Related genes will be overexpressed or silenced. ADAMs activity, binding and activation of receptors, expression and phosphorylation of intracellular molecules will be determined using an enzymatic assay, immunofluorescence and other molecular biological techniques. The aim of the project is to explore the role and signal transduction mechanisms of concentration-dependent bidirectional regulation of cardiac hypertrophy by TIMP3. This project will provide new insights into the role of TIMP3 in cardiac hypertrophy.