As a member of Sirtuins family, SIRT6 participates in the physiological and pathological progress of DNA repair, anti-aging, metabolism, and so on. Several studies have demonstrated that knockdown of SIRT6 inhibited the development of atherosclerosis (AS), indicated SIRT6 as a protective factor for AS. However, we confirmed SIRT6 was significantly overexpressed in human unstable carotid plaques compared with stable carotid plaques. This result indicated a more complex role of SIRT6 in AS. Furthermore, we constructed mice model with unstable carotid plaque and injected them with SIRT6 overexpressed adeno-associated virus (AAV-SIRT6). AAV-SIRT6 significantly promoted angiogenesis as well as hemorrhage in plaques. In vitro, we demonstrated overexpression of SIRT6 prevented HIF-1α from degradation by deubiquitination at K37 and K532 of HIF-1α, thus promoted the expression of HIF-1α under both normoxia and hypoxia in human umbilical vein endothelial cells (HUVECs). Through regulating HIF-1α, overexpression of SIRT6 promoted invasion, migration, proliferation, as well as tube formation ability of HUVECs. Interestingly, under different conditions, SIRT6 played different roles in the function of HUVECs. Under oxidative stress, another important pathological environment for AS, SIRT6 bound to the promoter of Catalase, a main reactive oxygen species scavenger, and depleted H3K56 acetylation, thus inhibited expression and activity of Catalase at the transcriptional level. Subsequently, inhibited Catalase promoted reactive oxygen species (ROS) under oxidative stress. Accumulated ROS further aggravated oxidative stress injury of HUVECs. On one hand, SIRT6 promoted angiogenesis in plaque via HIF-1α under hypoxia. On the other hand, SIRT6 promoted injury of neovascular via ROS under oxidative stress. It is this process of continuous growth and damage that leads to hemorrhage in carotid plaque. In conclusion, we innovatively confirmed SIRT6 promoted the angiogenesis and IPH via promoting HIF-1α and ROS in different environments, thus disclosed the unknowing danger of SIRT6.

SIRT6作为Sirtuins家族的一员，参与DNA修复、抗衰老、代谢等生理和病理过程。多项研究表明，敲除 SIRT6 可以抑制动脉粥样硬化 (AS) 的发展，表明 SIRT6 是 AS 的保护因子。然而，我们证实，与稳定的颈动脉斑块相比，SIRT6 在人类不稳定的颈动脉斑块中显着过度表达。这一结果表明 SIRT6 在 AS 中的作用更为复杂。此外，我们构建了颈动脉斑块不稳定的小鼠模型，并给它们注射了SIRT6过表达的腺相关病毒（AAV-SIRT6）。AAV-SIRT6 显着促进血管生成以及斑块出血。在体外，我们证明 SIRT6 的过表达可通过 HIF-1α K37 和 K532 的去泛素化阻止 HIF-1α 降解，从而促进人脐静脉内皮细胞（HUVEC）在常氧和缺氧条件下 HIF-1α 的表达。SIRT6的过表达通过调节HIF-1α促进HUVEC的侵袭、迁移、增殖以及管形成能力。有趣的是，在不同条件下，SIRT6对HUVECs的功能发挥着不同的作用。在氧化应激（AS的另一个重要病理环境）下，SIRT6与主要活性氧清除剂过氧化氢酶的启动子结合，并耗尽H3K56乙酰化，从而在转录水平抑制过氧化氢酶的表达和活性。随后，抑制过氧化氢酶会促进氧化应激下的活性氧（ROS）。ROS的积累进一步加剧了HUVECs的氧化应激损伤。一方面，SIRT6在缺氧条件下通过HIF-1α促进斑块内的血管生成。另一方面，SIRT6在氧化应激下通过ROS促进新生血管损伤。正是这种持续生长和损伤的过程导致颈动脉斑块出血。总之，我们创新性地证实了SIRT6在不同环境下通过促进HIF-1α和ROS促进血管生成和IPH，从而揭示了SIRT6不为人知的危险。