Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Anesthesiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Oxid Med Cell Longev. 2022 Jun 22;2022:2333848. doi: 10.1155/2022/2333848. eCollection 2022.
Angiogenesis plays a critical role in wound healing postmyocardial infarction (MI). However, there is still a lack of ideal angiogenic therapeutics for rescuing ischemic hearts clinically, suggesting that a more understanding regarding angiogenesis regulation is urgently needed. Heat shock protein A12A (HSPA12A) is an atypical member of the HSP70 family. Here, we demonstrated that HSPA12A was upregulated during endothelial tube formation, a characteristic of angiogenesis. Intriguingly, overexpression of HSPA12A promoted angiogenic characteristics including proliferation, migration, and tube formation of endothelial cells. By contrast, deficiency of HSPA12A impaired myocardial angiogenesis and worsened cardiac dysfunction post-MI in mice. The expression of genes related to angiogenesis (VEGF, VEGFR2, and Ang-1) was decreased by HSPA12A deficiency in MI hearts of mice, whereas their expression was increased by HSPA12A overexpression in endothelial cells. HSPA12A overexpression in endothelial cells increased phosphorylation levels and nuclear localization of AP-1, a transcription factor dominating angiogenic gene expression. Also, HSPA12A increased p38 and ERK phosphorylation levels, whereas inhibition of p38 or ERKs diminished the HSPA12A-promoted AP-1 phosphorylation and nuclear localization, as well as VEGF and VEGFR2 expression in endothelial cells. Notably, inhibition of either p38 or ERKs diminished the HSPA12A-promoted angiogenesis characteristics. The findings identified HSPA12A as a novel angiogenesis activator, and HSPA12A might represent a viable strategy for the management of myocardial healing in patients with ischemic heart diseases.
血管生成在心肌梗死后（MI）的伤口愈合中起着关键作用。然而，临床上仍然缺乏理想的血管生成治疗方法来拯救缺血的心脏，这表明我们迫切需要更多地了解血管生成的调节机制。热休克蛋白 A12A（HSPA12A）是 HSP70 家族的一个非典型成员。在这里，我们证明 HSPA12A 在血管生成的特征性内皮管形成过程中上调。有趣的是，HSPA12A 的过表达促进了内皮细胞的增殖、迁移和管形成等血管生成特征。相比之下，HSPA12A 缺陷会损害 MI 后小鼠的心肌血管生成并加重心脏功能障碍。在 MI 小鼠的心脏中，HSPA12A 缺陷降低了与血管生成相关的基因（VEGF、VEGFR2 和 Ang-1）的表达，而 HSPA12A 的过表达则增加了内皮细胞中这些基因的表达。HSPA12A 在内皮细胞中的过表达增加了转录因子 AP-1 的磷酸化水平和核定位，AP-1 主导着血管生成基因的表达。此外，HSPA12A 还增加了 p38 和 ERK 的磷酸化水平，而 p38 或 ERK 的抑制则减弱了 HSPA12A 促进的 AP-1 磷酸化和核定位，以及内皮细胞中 VEGF 和 VEGFR2 的表达。值得注意的是，抑制 p38 或 ERK 均可减弱 HSPA12A 促进的血管生成特征。这些发现确定了 HSPA12A 是一种新的血管生成激活剂，HSPA12A 可能代表了一种有前途的策略，可用于管理缺血性心脏病患者的心肌愈合。
