心脏重构是多种心血管疾病的共同中间环节，已有研究报道组蛋白甲基化对心脏重构具有重要作用，但不同的组蛋白甲基转移酶对心脏重构的影响不尽相同。本团队在发生心脏重构的人心脏移植标本中筛选发现组蛋白甲基转移酶SMYD2表达显著增加，进一步发现SMYD2与HDAC3存在相互作用，但SMYD2能否影响压力负荷诱导的心脏重构以及是否与HDAC3相关均未见报道。本项目拟通过四部分研究内容阐明SMYD2在压力负荷诱导的心脏重构中的作用及机制，首先检测SMYD2在正常和发生心脏重构的心脏中的表达模式；其次，在心肌细胞中敲低或过表达SMYD2明确其对心肌细胞肥大的影响及机制；第三，利用心脏特异性SMYD2敲除以及过表达小鼠明确其对心脏重构的影响及其机制；最后，利用SMYD2的抑制剂LLY-507干预压力负荷诱导的心脏重构，探索LLY-507治疗心脏重构的潜在临床应用价值，以期为临床干预心脏重构提供新靶点。

Cardiac remodeling is the common pathological process of a variety of cardiovascular diseases. Accumulating research demonstrated that histone methylation plays a critical role in cardiac remodeling, but their effects and mechanisms on heart were diverse dependent on different histone methyltransferases. Our preliminary experiment results showed that compared with normal heart, the protein level of SMYD2 was significantly increased in the heart of dilated cardiomyopathy patients, and SMYD2 interacts with deacetylase HDAC3. However, whether SMYD2 participates in pressure overload-induced cardiac remodeling and whether HDAC3 mediates its effects were not investigated. Therefore, in present proposal, four-part experiments were designed to clarify the role and mechanisms of SMYD2 on pressure overload-induced cardiac remodeling. First, we will detect the expression pattern of SMYD2 in the heart of human and mice with cardiac remodeling. Second, we will knock down or overexpress SMYD2 in primary cultured cardiomyocytes with lenti-shSMYD2 and lenti-SMYD2 to investigate the role and mechanism of SMYD2 on Ang II-induced cardiomyocyte hypertrophy. Third, cardiac-specific SMYD2 knockout and overexpression mice were used to ascertain the function and mechanism of SMYD2 on pressure overload-induced cardiac remodeling in vivo. Lastly, to explore the potential clinical application value of targeting SMYD2 in the treatment of cardiac remodeling, LLY-507, an inhibitor of SMYD2, will be used to remedy the mice with cardiac remodeling induced by pressure overload. This proposal tries to provide a novel target and new approach for clinical therapy of cardiac remodeling.