Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
J Mol Cell Cardiol. 2011 Nov;51(5):821-9. doi: 10.1016/j.yjmcc.2011.07.030. Epub 2011 Aug 7.
Heat shock transcription factor 1 (HSF1) plays an important role not only in excise-induced cardiac hypertrophy but also in protection against pressure overload-induced cardiac dysfunction. However, the mechanism is not completely understood. We here elucidate the potential mechanisms by which HSF1 protects against pressure overload-induced cardiac remodeling and dysfunction. A sustained constriction of transverse aorta (TAC) was imposed to HSF1 transgenic (TG), knockout (KO) and their littermate wild type (WT) male mice. Four weeks later, adaptive responses to TAC, such as cardiac hypertrophy, contractility and angiogenesis evaluated by echocardiography, catheterization, coronary perfusion pressure and immunohistochemistry were well preserved in TG but not in KO compared with WT mice. An angiogenesis inhibitor TNP-470 abrogated all these adaptive responses in TG mice, while cardiac transfection of VEGF with angiopoietin-1 rescued the broken heart in KO mice. In response to TAC, p53 was downregulated and hypoxia-inducing transcription factor-1 (HIF-1) was upregulated not only in the heart but also in the cultured cardiac endothelial cells (EC) of TG mice as compared to WT mice whereas these changes became opposite in KO mice. A small interfering RNA (siRNA) of HIF-1 but not a p53 gene impaired the adaptive responses of the heart and EC in TG mice, and a siRNA of p53 but not a HIF-1 gene significantly reversed the heart and EC disorders in KO mice after TAC. We conclude that HSF1 promotes cardiac angiogenesis through suppression of p53 and subsequent upregulation of HIF-1 in endothelial cells during chronic pressure overload, leading to the maintenance of cardiac adaptation.
热休克转录因子 1（HSF1）不仅在切除诱导的心脏肥大中发挥重要作用，而且在保护压力超负荷诱导的心脏功能障碍中也发挥重要作用。然而，其机制尚不完全清楚。我们在此阐明了 HSF1 保护压力超负荷诱导的心脏重构和功能障碍的潜在机制。通过对 HSF1 转基因（TG）、敲除（KO）及其同窝野生型（WT）雄性小鼠的横主动脉（TAC）进行持续缩窄，4 周后，通过超声心动图、导管插入术、冠状动脉灌注压和免疫组织化学评估 TAC 引起的适应性反应，如心脏肥大、收缩力和血管生成，在 TG 中得到了很好的保留，但在 KO 中与 WT 相比则没有保留。血管生成抑制剂 TNP-470 阻断了 TG 小鼠的所有这些适应性反应，而心脏转染血管内皮生长因子与血管生成素-1则挽救了 KO 小鼠的衰竭心脏。与 WT 小鼠相比，在 TG 小鼠的心脏和培养的心脏内皮细胞（EC）中，p53 被下调，低氧诱导转录因子-1（HIF-1）被上调，不仅在心脏中，而且在心脏中也是如此。在 KO 小鼠中，这些变化则相反。与 WT 小鼠相比，用 HIF-1 的小干扰 RNA（siRNA）而非 p53 基因损害了 TG 小鼠心脏和 EC 的适应性反应，而用 p53 的 siRNA 而非 HIF-1 基因则显著逆转了 TAC 后 KO 小鼠的心脏和 EC 异常。我们的结论是，在慢性压力超负荷下，HSF1 通过抑制内皮细胞中的 p53，随后上调 HIF-1，促进心脏血管生成，从而维持心脏的适应性。
