血管内皮细胞（VECs）衰老是心血管疾病发病的关键。前期已发现动脉斑块中组蛋白甲基转移酶SMYD3上调并伴随衰老标记物和衰老分泌炎症表型增加；在血管紧张素II（Ang II）诱导VECs衰老中同样伴有SMYD3和衰老分泌炎症表型，沉默SMYD3可逆转其衰老及其表型。但SMYD3在VECs衰老及衰老相关心血管疾病中的作用和表观遗传机制仍不明确。据此提出“SMYD3调控组蛋白甲基化修饰增强其下游靶基因转录表达，促进VECs衰老及相关心血管疾病的发生发展”的假说。拟用体外VECs衰老和临床动脉粥样硬化样本、体内Ang II诱导小鼠血管衰老模型及高脂诱导ApoE-/-小鼠动脉粥样硬化模型，结合构建VECs特异性SMYD3-/-模式动物和慢病毒SMYD3沉默/过表达技术，阐明SMYD3促进VECs衰老加速血管功能紊乱作用，并明确SMYD3增强NF-κB转录的表观遗传机制，为心血管疾病的防治提供新靶点

Vascular endothelial senescence plays a pivotal role in the development of cardiovascular diseases. Our previous results have demonstrated that the upregulation of histone methyltransferase SMYD3 was observed in atherosclerotic arteries of patients, which was accompanying with increase of senescent makers and senescence-associated secretory phenotype. The similar results were also observed in angiotensin II (Ang II)-induced vascular endothelial senescence. The events were reversed by SMYD3 knockdown strategy. However, the role and epigenetic mechanisms of SMYD3 in endothelial senescence and senescence-related cardiovascular diseases remain unclear. Herein, we propose the following hypothesis that SMYD3 promoted the development of vascular endothelial senescence and senescence-related cardiovascular disease through modulation the histone modification. In our follow-up study, we will elucidate that SMYD3 accelerated the development of endothelial senescence and senescence-associated cardiovascular diseases and underlying epigenetic mechanism. 1) Senescence of rat aortic endothelial cells induced by Ang II and senescent artery endothelial cells isolated from atherosclerotic arteries of patients and senescent makers, endothelial function, senescence-associated secretory phenotype were measured to demonstrated that SMYD3 accelerated endothelial senescence. Lentiviral SMYD3 overexpression or knockdown will be used. 2) To elucidate the role of SMYD3 in vascular dysfunction, vascular dysfunction was induced by Ang II in endothelium-specific SMYD3 knockout mice. Vascular function, vascular endothelial senescence, et al. in artery were compared by combining lentiviral-mediated SMYD3 overexpression/knockdown. 3) atherosclerosis was induced by high fat diet in ApoE-/- mice and the plaque size，fibrous cap stability, vascular endothelial senescence, inflammatory mediators in atherosclerotic vascular were measured. A positive correlation of SMYD3 expression with atherosclerosis and a key role of SMYD3 in high fat diet-induced atherosclerosis were identified by combining lentiviral-mediated SMYD3 overexpression/knockdown. 4) In above-mentioned cell and animal models by various molecular biology techniques, we further verify that the epigenetic mechanism is that SMYD3 strengthens NF-κB transcriptional activity, which enhances it’s binding to the senescent makers and SASP promoter and increases senescent makers and SASP transcription. These findings will shed lights on the mechanistic insights during development of senescence-related cardiovascular diseases and suggest that SMYD3 serves as a novel therapeutic target for treating senescence-related cardiovascular diseases..